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NF-κB in rheumatoid arthritis: a pivotal regulator of inflammation, hyperplasia, and tissue destruction

NF-κB in rheumatoid arthritis: a pivotal regulator of inflammation, hyperplasia, and tissue... The transcription factor NF-kB has been well recognized as a pivotal regulator of inflammation in rheumatoid arthritis (RA), but recent developments revealed a broad involvement of NF-kB in other aspects of RA pathology, including development of T helper 1 responses, activation, abnormal apoptosis and proliferation of RA fibroblast-like synovial cells, and differentiation and activation of bone resorbing activity of osteoclasts. In agreement with this, studies in animal models of RA have demonstrated the high therapeutic efficacy of specific inhibitors of NF-kB pathway, indicating the feasibility of anti-NF-kB therapy for human disease. Keywords: apoptosis, hyperplasia, inflammation, inhibitors, nuclear factor NFkB, rheumatoid arthritis, therapy Introduction C/EBPs, STATs, NF-AT, and NF-kB, appear to play a Chronic inflammation perpetuates and amplifies itself major role in the regulation of inflammatory genes. This through the numerous autocrine and paracrine loops of suggests that neutralization of these transcription factors cytokines, acting on the cells within the lesion. The vicious may provide an efficacious therapeutic strategy. A pivotal circle can be broken either by neutralizing the biological role for the transcription factor NF-kB in regulation of activities of extracellular inflammatory mediators or by inflammation has been well recognized [1,2]. I attempted, inhibiting cytokine production. The pattern of gene expres- in a recent general article, to summarize the latest devel- sion is controlled by transcription factors, which relay into opments in the field and to discuss the feasibility of anti- the nucleus signals emanating from the cytoplasmic mem- NF-kB therapy for chronic inflammation [3]. The present brane. In the nucleus, transcription factors selectively bind review focuses on the role of NF-kB in the particular fea- their cognate sites in the regulatory elements of targeted tures of RA pathology. genes and activate or repress transcription. It appears that the complexity of inflammatory pathways is significantly The NF-k kB signaling pathway reduced on the level of transcription factors. Whereas the NF-kB is a collective name for dimeric transcription cell within the inflammatory lesion is subjected to many factors comprised of the Rel family of proteins that include dozens, perhaps hundreds, of extracellular stimuli, only a RelA (p65), c-Rel, RelB, NF-kB1 (p50), and NF-kB2 (p52) handful of inducible transcription factors, including AP-1, [4]. The most abundant form found in stimulated cells is APC = antigen presenting cell; CIA = collagen-induced arthritis; FLS = fibroblast-like synovial cells; IKK = IkB kinase; MMP = matrix metallo- proteinases; NFkB = nuclear factor kappa B; PDGF = platelet-derived growth factor; PI(3)K = phosphatidylinositol 3-kinase; RA = rheumatoid arthritis; SCW = streptococcal cell wall; Th cells = T helper cells; TNF = tumor necrosis factor. commentary review reports primary research Available online http://arthritis-research.com/content/3/4/200 the RelA/NF-kB1 (p65/p50) heterodimer, often referred to activity in RA patients, but not in osteoarthritis patients [9]. as a ‘classic’ NF-kB. In unstimulated cells, NF-kB resides in Immunohistochemical studies detected nuclear RelA the cytoplasm in a latent form, and must translocate to the (p65) and NF-kB1 (p50) mostly in RA endothelium and nucleus to function. The cytoplasmic retention of NF-kB is synovial lining, particularly in CD14-positive cells, and no provided by its interaction with inhibitory proteins known as staining in the normal synovium [10]. Immunostaining with IkB. Stimulation leads to a phosphorylation-targeted protea- antibodies against the ‘active’ (dissociated from IkB) somal degradation of IkB, allowing the ‘active’ NF-kB to NF-kB similarly revealed the presence of active NF-kB in enter the nucleus and initiate transcription. the nuclei of macrophage-like synoviocytes in synovial lining and in vascular endothelium. The active NF-kB was The signal-induced IkB processing involves the consecu- found in both RA and osteoarthritis samples, although the tive steps of IkB phosphorylation, ubiquitination, and pro- pattern was different: patients with acute RA more com- teasomal degradation, which are controlled by three large monly showed vessel staining and, conversely, showed multiprotein complexes; namely, IkB kinase (IKK), or signal- less frequent staining of the synovial lining as compared some, IkB ubiquitin ligase, and 26S proteasome [5]. The with osteoarthritis patients [11]. Miyazawa et al used an IkB ubiquitin ligase and 26S proteasome are considered alternative approach with a NF-kB reporter gene construct mostly constitutively active, while IKK activity is rapidly to analyze NF-kB-dependent transcription in single clones induced in response to stimulation. The core components of primary RA fibroblast-like synovial cells (FLS) in vitro. of the signalsome include the catalytic subunits IKKa/IKK-1 Constitutively active NF-kB was detected in some of the and IKKb/IKK-2, and a scaffold protein IKKk/NEMO that clones and, noteworthy, these clones spontaneously pro- links the catalytic kinase subunits with the upstream activa- duced large amounts of IL-6 [12]. These findings combine tors. Both IKKa and IKKb can phosphorylate IkB in vitro, to provide compelling evidence that NF-kB activation is a but knockout studies indicate that IKKb has a pivotal role in common feature of human RA synovium. Activation of cytokine-inducible activation of NF-kB [5]. NF-kB has also been detected in different animal models of RA, including adjuvant arthritis in rats [13], pristane- In addition to the spatial control of NF-kB function, the induced [14] and streptococcal cell wall (SCW)-induced ability of nuclear NF-kB to initiate transcription is regulated arthritis in rats [14,15], and collagen-induced arthritis by interactions with numerous transcriptional coactivators (CIA) in mice [16]. and basal transcriptional machinery. The pathways con- trolling NF-kB nuclear translocation and its transcription NF-k kB and synovial inflammation function are regulated independently, but act in synergy in Initiation of chronic inflammation in RA is associated with the activation of NF-kB-dependent gene expression [6]. development of an autoimmune response that progresses to a sustained, self-perpetuated inflammation. Experimen- NF-kB can be activated by a variety of pathogenic stimuli, tal evidence suggests that NF-kB activation plays a pivotal including bacterial products and viral proteins, cytokines, role both at the stage of initiation and the stage of perpet- growth factors, radiation, ischemia/reperfusion, and oxida- uation of chronic inflammation in RA. tive stress. The coordinated activation of NF-kB that occurs in almost every cell type involved in inflammatory NF-k kB in the initiation of chronic response, including neutrophils, macrophages, lympho- inflammation cytes, and endothelial, epithelial, and mesenchymal cells, The interaction of the antigen presenting cell (APC) and T is an integral part of the defensive response to pathogens cell causes NF-kB activation in both cell types. NF-kB and stress. The activation of NF-kB is required to induce activation is triggered in T cells by the engagement of the expression of diverse inflammatory and immune response T cell receptor and the CD28 receptor with their ligands, mediators. More than 150 NF-kB responsive genes have MHC class II, and the costimulatory molecules CD80 and been identified, among them cytokines, chemokines, cell CD86 presented by APCs. The T cell receptor and CD28 adhesion molecules, and growth factors [7]. A few exam- synergize in induction of the NF-kB-dependent genes ples of inducers and targets of NF-kB are presented in required for T cell activation and proliferation, such as IL-2, Figure 1. It is worth noting that the list of inducers and IL-2 receptor (IL-2R), and IFNg [17,18]. Activated T cells, targets of NF-kB almost perfectly matches the list of in turn, elicit NF-kB activation in APCs. The molecules of pivotal mediators of RA pathology. the tumor necrosis factor (TNF) superfamily, CD40 ligand and TRANCE (TNF-related activation-induced cytokine) NF-k kB is activated in RA (also known as RANKL [receptor activator of NF-kB Activated NF-kB has been detected in human synovial ligand]) or ODF (osteoclast differentiation factor), are tissue on the early stage of joint inflammation [8], as well expressed by activated T cells. Their interaction with APC as in specimens obtained at the late stages of the disease. receptors CD40 and RANK induces NF-kB activation that Analyses of nuclear extracts from synovial explants promotes survival and augments the ability of the APC to revealed the presence of increased NF-kB DNA binding stimulate T cell proliferation and activation, conceivably by Arthritis Research Vol 3 No 4 Makarov Figure 1 Inducers and targets of NF-kB. bFGF, Basic fibroblast growth factor; CD40L, CD40 ligand; COX-2, cyclooxygenase-2; GM-CSF, granulocyte- macrophage colony-stimulating factor; iNOS, inducible nitric oxide synthetase; LPS, lipopolysaccharide; MCP-1, monocyte chemoattractant protein-1; RANKL, receptor activator of NF-kB ligand; TRANCE, TNF-related activation-induced cytokine; VEGF, vascular endothelial growth factor. upregulating the expression of NF-kB-dependent mole- ent immune responses: Th1 (IFNg and IL-12 dominant) cules MHC class II, CD80, and CD86 [19–22]. The cells mediate cellular immunity and activate macrophages, importance of NF-kB activation in immune response was and they are considered proinflammatory; Th2 (IL-4 and supported by the observations in knockout mice. Inactiva- IL-5 dominant) cells, which potentiate antiparasite and –/– –/– tion of RelB and NF-kB2 in relb and nfkb2 caused an humoral immunity, and inhibit macrophage activation, are impairment of APC function. The loss of NF-kB1 and c-Rel considered anti-inflammatory. As NF-kB controls the –/– –/– in nfkb1 and rel mice resulted in multiple defects in expression of Th1 cytokines IL-2, IFNg, and IL-12, activa- the activation of T and B cells, and weakened responses tion of NF-kB should facilitate Th1 subset development. to pathogens [23]. Indeed, transgenic mice expressing, in the T lineage, an inhibitor of NF-kB (a nondegradable mutant of IkBa, also NF-k kB facilitates T helper 1 subset development called ‘super-repressor’ IkBa [srIkBa]), had weakened After activation, CD4 T helper (Th) cells can differentiate Th1 and enhanced Th2 responses [24,25]. T cells from into Th1 or Th2 effector subsets. These two types of cells transgenic mice expressing Rac2, an upstream NF-kB produce distinct profiles of cytokines and regulate differ- activator, accordingly developed Th1 type responses [26]. commentary review reports primary research Available online http://arthritis-research.com/content/3/4/200 NF-k kB and the perpetuation of chronic for proliferation, it causes cell death unless certain survival inflammation factors are provided. PDGF is one such factor that over- Secreted products of activated T cells and direct cell–cell comes the pro-apoptotic proclivity of c-Myc. We found contacts induce activation of macrophages, the major pro- that blocking NF-kB activation abrogated the protective ducers of inflammatory cytokines in RA synovium. NF-kB effect of PDGF, indicating that, in PDGF signaling, NF-kB controls the expression of cytokines IL-1b and TNFa, the transmits two signals: one is required for the induction of essential mediators of inflammation in RA. TNFa and IL-1 c-Myc; and the second is an anti-apoptotic signal that neu- are potent inducers of NF-kB activation, suggesting an tralizes c-Myc cytotoxicity, conceivably by inducing the interdependence of persistent NF-kB activation and sus- expression of a protective gene (or multiple genes) [32]. tained levels of IL-1 and TNFa. Indeed, expression of As c-Myc is heavily overexpressed in RA synovium, NF-kB srIkBa abrogated the induction of IL-1b and TNFa in activation may contribute to synovial hyperplasia by inhibit- human macrophages and primary FLS [14,27]. A recent ing c-Myc-induced apoptosis and promoting proliferation. study by Aupperle et al indicates that, in RA FLS, A point of interest is that the pathway via which PDGF IKKb/IKK-2 is the principal kinase in activation of NF-kB in induced NF-kB activation involved phosphatidylinositol 3- response to IL-1 and TNFa. Expression of a DN mutant kinase (PI(3)K) and protein kinase B/Akt (see later). As the form of IKK-2 inhibited cytokine-inducible activation of PI(3)K/Akt pathway has been implicated in the pathogene- NF-kB and abrogated synthesis of IL-6 and IL-8, as well sis of numerous human malignancies, this suggests that as expression of ICAM-1 and collagenase-1. In contrast, similar mechanisms may operate in the promotion of the DN IKKa/IKK-1 had no effect [28]. The notion that hyperplasia in RA and cancer. IKKb/IKK-2 is the key convergence pathway for cytokine- induced NF-kB activation is consistent with results of Apoptosis genetic studies in IKK knockout mice [5]. Many pro-apoptotic stimuli, including TNFa, radiation, and chemotherapy, induce NF-kB activation. NF-kB activation It is worthy of note that suppression of NF-kB inhibited delivers, in most cell types, an anti-apoptotic signal that expression of many proinflammatory molecules, including counteracts cell death. NF-kB suppression of apoptosis IL-1, TNFa, IL-6, IL-8, ICAM-1 and VCAM-1, but had little, appears to be a transcriptional event since it activates if any, effect on the expression of anti-inflammatory expression of anti-apoptotic genes TRAF1 and TRAF2, cytokines IL-10 and IL-1 receptor antagonist [14,29–31]. c-IAP1 and c-IAP2, the Bcl-2 homologs A1/Bfl-1 and Bcl- This suggests that NF-kB activation facilitates the xL, IEX-1, and XIAP (reviewed in [35]). In our studies, impaired balance of proinflammatory and anti-inflammatory blocking NF-kB activation in primary rat SCW FLS molecules in the arthritic joint. strongly potentiated the cytotoxicity of TNFa and FasL. Consistent with this, administration of distinct inhibitors of NF-k kB and hyperplasia NF-kB (proteasomal inhibitors and adenoviral gene trans- Normal synovium is a delicate tissue lining the joint fer of srIkBa) in vivo resulted in accelerated apoptosis in capsule but, in RA, the synovium transforms into an joints of rats with pristane-induced and SCW-induced aggressive, tumor-like structure called pannus, which arthritis [14]. These studies are in agreement with that invades and erodes the joint. Experimental evidence sug- published by Zhang et al, who observed that NF-kB acti- gests that NF-kB activation may facilitate synovial hyper- vation was required to protect RA FLS against the cytotox- plasia by promoting proliferation and inhibiting apoptosis icity of TNFa in a human RA/SCID mouse model, of RA FLS. presumably through induction of anti-apoptotic protein XIAP [36]. These findings indicate an important role for Proliferation NF-kB in protecting FLS against apoptosis in RA syn- NF-kB serves as a positive regulator of cell growth in ovium, conceivably by inhibiting the cytotoxicity of TNFa myoblasts and fibroblasts by inducing the expression of and FasL. Because TNFa is a potent mitogen in RA FLS, c-Myc and cyclin D1, proteins required for cell cycle pro- NF-kB appears as a master switch determining whether gression [32–34]. Our studies in primary rat FLS have TNFa exerts mitogenic or pro-apoptotic effects. shown that stimulation with platelet-derived growth factor (PDGF) and basic fibroblast growth factor induced NF-kB Recent work from our laboratory and by other workers has, activation, which was required for induction of c-Myc and as already mentioned, established NF-kB as a target of the DNA synthesis [32] (J Romashkova, S Makarov, unpub- PI(3)/Akt pathway that has a prominent role in cell survival lished observations). In contrast, the mitogenic activity of and proliferation in cancer. The PI(3)K/Akt pathway has insulin-like growth factor-1, which did not activate NF-kB, been shown to mediate activation of NF-kB in response to was not influenced by NF-kB inhibitors (J Romashkova, S a wide variety of stimuli, including PDGF [32], TNFa [37], Makarov, unpublished observations). Another function of IL-1 [38], bradykinin [39], and oncogenic H-Ras [40] and NF-kB in mitogenic signaling in FLS is to protect cells Her-2/neu [41]. Akt-dependent NF-kB activation has been against cytotoxicity of c-Myc. Although c-Myc is required shown to mediate anti-apoptotic functions of PDGF [32] Arthritis Research Vol 3 No 4 Makarov and Her-2/neu [41], and to inhibit cell death induced by cytokines IL-1a and IL-1b, TNFa, IL-6, and IL-17 [53,54]. deregulated c-myc [32], H-Ras [40], and TNFa [41]. Pre- The contacts with activated T cells and osteoblast/stromal cisely how Akt activates NF-kB-dependent transcription is cells expressing high levels of TRANCE/RANKL/ODF a matter of debate. Several groups, including that of the promote osteoclast maturation and induce bone resorbing present author, demonstrated an involvement of IKK, thus activity, while administration of osteoprotegrin, a soluble implicating IkB-dependent mechanisms [32,37,39,41,42], decoy receptor for RANKL, prevents osteoclast differenti- while results by other workers demonstrate IkB-indepen- ation and precludes bone loss in animal arthritis [20,55]. dent mechanisms, in which Akt potentiates the transcrip- The critical importance of NF-kB in bone turnover was tional function of NF-kB [38,40]. It is possible that the underscored by the observations in double-knockout –/– –/– mechanisms connecting Akt with NF-kB, as well as the nfkb1 nfkb2 mice that develop osteopetrosis owing to contribution of NF-kB pathway in the anti-apoptotic func- accumulation of immature osteoclasts [56]. tion of Akt, are cell type and stimulus specific. A role for Akt in the pathogenesis of RA and the contribution of Akt The NF-k kB pathway as a therapeutic target to NF-kB activation in RA synovium are not known, but Many conventional anti-inflammatory and anti-rheumatic there is circumstantial evidence that this link may exist. drugs, including glucocorticoids, aspirin, sodium salicy- The activity of the PI(3)K/Akt pathway is negatively regu- late, sulfosalazine, and gold compounds, are inhibitors of lated by the phosphatase PTEN, a tumor suppressor fre- NF-kB activation. The list of therapeutics that inhibit quently inactivated in human malignancies [43] and in NF-kB also includes numerous natural and synthetic some autoimmune diseases, such as Cowden disease antioxidants, immunosuppressants, and natural plant com- and Sjögren’s syndrome [44]. The importance of the pounds, suggesting that the ability to suppress NF-kB PTEN-PI(3)K/Akt connection in autoimmune disease was activation at least partially accounts for their therapeutic +/– demonstrated by observations in PTEN heterozygous effects [57]. This interpretation, however, is complicated mice that exhibited defects in Fas-induced apoptosis and by the fact that most of the conventional drugs are not developed autoimmune disease [45], and in PI(3)K trans- very potent inhibitors of NF-kB, and that they can also genic mice that developed strikingly similar pathology affect other signaling pathways. More clear answers were [46]. Although PTEN mutations were not found in RA, the obtained using animals with genetically inactivated NF-kB –/– expression of PTEN is strikingly reduced in RA synovial signaling. Inactivation of c-Rel and NF-kB1 in rel and –/– lining [47], suggesting that deregulated PTEN may result nfkb1 knockout mice rendered the animals refractory to in activation of the PI(3)K/Akt pathway and contribute to development of CIA [58]. Transgenic mice expressing activation of NF-kB. The role of Akt and the Akt–NF-kB srIkBa in the T lineage were similarly refractory to CIA connection in RA clearly merits further investigation. [25]. These genetic studies are in a good agreement with the experiments that utilized highly specific inhibitors of NF-k kB and tissue remodeling NF-kB. In our studies, liposomal delivery of NF-kB decoys FLS are considered the major effectors of RA joint (double-stranded oligonucleotides containing NF-kB destruction. Inflammatory milieu in the RA joint results in a binding sites) effectively prevented the recurrence of highly invasive phenotype of RA FLS. Several lines of evi- SCW arthritis in rats. Intriguingly, the suppression of dence suggest that NF-kB activation contributes to the arthritis was evident not only in the ipsilateral, treated destructive potential of RA FLS. First, NF-kB mediates joints, but also in the contralateral, untreated joints, indi- transcriptional activation of several matrix metallopro- cating systemic effects of local anti-NF-kB therapy [14]. teinases (MMP). The promoter of MMP-1 has a NF-kB Administration of NF-kB decoys in a similar study signifi- binding site that is required for the induction of MMP-1 by cantly reduced the severity of CIA in rats, and inhibited the IL-1b [48]. Furthermore, NF-kB activation was found nec- production of IL-1 and TNFa within the joints [59]. In a essary for the induction of MMP-3, MMP-9, and MMP-13 study by Palombella et al, a proteasomal inhibitor of IkB expression [49–51]. Second, NF-kB activation is neces- degradation afforded protection against SCW-induced sary for the induction of cyclooxygenase-2 and inducible arthritis in rat [15]. Together, these animal studies strongly nitric oxide synthetase, the enzymes that catalyze synthe- support the feasibility of using NF-kB inhibitors in RA. sis of proinflammatory prostaglandins and nitric oxide metabolites [7]. Finally, NF-kB activation is required for the The prospects of anti-NF-k kB therapy for RA induction of vascular endothelial growth factor, an The efficacy of anti-NF-kB therapy in animal models of RA endothelial cell-specific mitogen and a pivotal regulator of allows for optimism, but many questions remain to be angiogenesis in RA [52]. answered. First, future therapeutic applications will require development of specific and potent inhibitors of the NF-kB Osteoclast is another cell type in which NF-kB activation pathway. Second, the safety of a long-term use of specific may have a prominent role in RA joint destruction. Bone NF-kB inhibitors remains to be elucidated. The lessons marrow-derived osteoclast precursors are recruited to RA from genetic studies revealed that basal NF-kB activity is synovium by elevated levels of NF-kB-dependent required for normal development, particularly for protection commentary review reports primary research Available online http://arthritis-research.com/content/3/4/200 of liver against apoptosis, and that inactivation of the NF- 12. Miyazawa K, Mori A, Yamamoto K, Okudaira H: Constitutive tran- scription of the human interleukin-6 gene by rheumatoid syn- kB pathway may be associated with detrimental side oviocytes: spontaneous activation of NF-kappa B and CBF1. effects (reviewed in [23]). 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NF-κB in rheumatoid arthritis: a pivotal regulator of inflammation, hyperplasia, and tissue destruction

Makarov, Sergei S
Arthritis Research & Therapy , Volume 3 (4): 7 – Jun 1, 2001
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Springer Journals
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2001 BioMed Central Ltd
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10.1186/ar300
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Abstract

The transcription factor NF-kB has been well recognized as a pivotal regulator of inflammation in rheumatoid arthritis (RA), but recent developments revealed a broad involvement of NF-kB in other aspects of RA pathology, including development of T helper 1 responses, activation, abnormal apoptosis and proliferation of RA fibroblast-like synovial cells, and differentiation and activation of bone resorbing activity of osteoclasts. In agreement with this, studies in animal models of RA have demonstrated the high therapeutic efficacy of specific inhibitors of NF-kB pathway, indicating the feasibility of anti-NF-kB therapy for human disease. Keywords: apoptosis, hyperplasia, inflammation, inhibitors, nuclear factor NFkB, rheumatoid arthritis, therapy Introduction C/EBPs, STATs, NF-AT, and NF-kB, appear to play a Chronic inflammation perpetuates and amplifies itself major role in the regulation of inflammatory genes. This through the numerous autocrine and paracrine loops of suggests that neutralization of these transcription factors cytokines, acting on the cells within the lesion. The vicious may provide an efficacious therapeutic strategy. A pivotal circle can be broken either by neutralizing the biological role for the transcription factor NF-kB in regulation of activities of extracellular inflammatory mediators or by inflammation has been well recognized [1,2]. I attempted, inhibiting cytokine production. The pattern of gene expres- in a recent general article, to summarize the latest devel- sion is controlled by transcription factors, which relay into opments in the field and to discuss the feasibility of anti- the nucleus signals emanating from the cytoplasmic mem- NF-kB therapy for chronic inflammation [3]. The present brane. In the nucleus, transcription factors selectively bind review focuses on the role of NF-kB in the particular fea- their cognate sites in the regulatory elements of targeted tures of RA pathology. genes and activate or repress transcription. It appears that the complexity of inflammatory pathways is significantly The NF-k kB signaling pathway reduced on the level of transcription factors. Whereas the NF-kB is a collective name for dimeric transcription cell within the inflammatory lesion is subjected to many factors comprised of the Rel family of proteins that include dozens, perhaps hundreds, of extracellular stimuli, only a RelA (p65), c-Rel, RelB, NF-kB1 (p50), and NF-kB2 (p52) handful of inducible transcription factors, including AP-1, [4]. The most abundant form found in stimulated cells is APC = antigen presenting cell; CIA = collagen-induced arthritis; FLS = fibroblast-like synovial cells; IKK = IkB kinase; MMP = matrix metallo- proteinases; NFkB = nuclear factor kappa B; PDGF = platelet-derived growth factor; PI(3)K = phosphatidylinositol 3-kinase; RA = rheumatoid arthritis; SCW = streptococcal cell wall; Th cells = T helper cells; TNF = tumor necrosis factor. commentary review reports primary research Available online http://arthritis-research.com/content/3/4/200 the RelA/NF-kB1 (p65/p50) heterodimer, often referred to activity in RA patients, but not in osteoarthritis patients [9]. as a ‘classic’ NF-kB. In unstimulated cells, NF-kB resides in Immunohistochemical studies detected nuclear RelA the cytoplasm in a latent form, and must translocate to the (p65) and NF-kB1 (p50) mostly in RA endothelium and nucleus to function. The cytoplasmic retention of NF-kB is synovial lining, particularly in CD14-positive cells, and no provided by its interaction with inhibitory proteins known as staining in the normal synovium [10]. Immunostaining with IkB. Stimulation leads to a phosphorylation-targeted protea- antibodies against the ‘active’ (dissociated from IkB) somal degradation of IkB, allowing the ‘active’ NF-kB to NF-kB similarly revealed the presence of active NF-kB in enter the nucleus and initiate transcription. the nuclei of macrophage-like synoviocytes in synovial lining and in vascular endothelium. The active NF-kB was The signal-induced IkB processing involves the consecu- found in both RA and osteoarthritis samples, although the tive steps of IkB phosphorylation, ubiquitination, and pro- pattern was different: patients with acute RA more com- teasomal degradation, which are controlled by three large monly showed vessel staining and, conversely, showed multiprotein complexes; namely, IkB kinase (IKK), or signal- less frequent staining of the synovial lining as compared some, IkB ubiquitin ligase, and 26S proteasome [5]. The with osteoarthritis patients [11]. Miyazawa et al used an IkB ubiquitin ligase and 26S proteasome are considered alternative approach with a NF-kB reporter gene construct mostly constitutively active, while IKK activity is rapidly to analyze NF-kB-dependent transcription in single clones induced in response to stimulation. The core components of primary RA fibroblast-like synovial cells (FLS) in vitro. of the signalsome include the catalytic subunits IKKa/IKK-1 Constitutively active NF-kB was detected in some of the and IKKb/IKK-2, and a scaffold protein IKKk/NEMO that clones and, noteworthy, these clones spontaneously pro- links the catalytic kinase subunits with the upstream activa- duced large amounts of IL-6 [12]. These findings combine tors. Both IKKa and IKKb can phosphorylate IkB in vitro, to provide compelling evidence that NF-kB activation is a but knockout studies indicate that IKKb has a pivotal role in common feature of human RA synovium. Activation of cytokine-inducible activation of NF-kB [5]. NF-kB has also been detected in different animal models of RA, including adjuvant arthritis in rats [13], pristane- In addition to the spatial control of NF-kB function, the induced [14] and streptococcal cell wall (SCW)-induced ability of nuclear NF-kB to initiate transcription is regulated arthritis in rats [14,15], and collagen-induced arthritis by interactions with numerous transcriptional coactivators (CIA) in mice [16]. and basal transcriptional machinery. The pathways con- trolling NF-kB nuclear translocation and its transcription NF-k kB and synovial inflammation function are regulated independently, but act in synergy in Initiation of chronic inflammation in RA is associated with the activation of NF-kB-dependent gene expression [6]. development of an autoimmune response that progresses to a sustained, self-perpetuated inflammation. Experimen- NF-kB can be activated by a variety of pathogenic stimuli, tal evidence suggests that NF-kB activation plays a pivotal including bacterial products and viral proteins, cytokines, role both at the stage of initiation and the stage of perpet- growth factors, radiation, ischemia/reperfusion, and oxida- uation of chronic inflammation in RA. tive stress. The coordinated activation of NF-kB that occurs in almost every cell type involved in inflammatory NF-k kB in the initiation of chronic response, including neutrophils, macrophages, lympho- inflammation cytes, and endothelial, epithelial, and mesenchymal cells, The interaction of the antigen presenting cell (APC) and T is an integral part of the defensive response to pathogens cell causes NF-kB activation in both cell types. NF-kB and stress. The activation of NF-kB is required to induce activation is triggered in T cells by the engagement of the expression of diverse inflammatory and immune response T cell receptor and the CD28 receptor with their ligands, mediators. More than 150 NF-kB responsive genes have MHC class II, and the costimulatory molecules CD80 and been identified, among them cytokines, chemokines, cell CD86 presented by APCs. The T cell receptor and CD28 adhesion molecules, and growth factors [7]. A few exam- synergize in induction of the NF-kB-dependent genes ples of inducers and targets of NF-kB are presented in required for T cell activation and proliferation, such as IL-2, Figure 1. It is worth noting that the list of inducers and IL-2 receptor (IL-2R), and IFNg [17,18]. Activated T cells, targets of NF-kB almost perfectly matches the list of in turn, elicit NF-kB activation in APCs. The molecules of pivotal mediators of RA pathology. the tumor necrosis factor (TNF) superfamily, CD40 ligand and TRANCE (TNF-related activation-induced cytokine) NF-k kB is activated in RA (also known as RANKL [receptor activator of NF-kB Activated NF-kB has been detected in human synovial ligand]) or ODF (osteoclast differentiation factor), are tissue on the early stage of joint inflammation [8], as well expressed by activated T cells. Their interaction with APC as in specimens obtained at the late stages of the disease. receptors CD40 and RANK induces NF-kB activation that Analyses of nuclear extracts from synovial explants promotes survival and augments the ability of the APC to revealed the presence of increased NF-kB DNA binding stimulate T cell proliferation and activation, conceivably by Arthritis Research Vol 3 No 4 Makarov Figure 1 Inducers and targets of NF-kB. bFGF, Basic fibroblast growth factor; CD40L, CD40 ligand; COX-2, cyclooxygenase-2; GM-CSF, granulocyte- macrophage colony-stimulating factor; iNOS, inducible nitric oxide synthetase; LPS, lipopolysaccharide; MCP-1, monocyte chemoattractant protein-1; RANKL, receptor activator of NF-kB ligand; TRANCE, TNF-related activation-induced cytokine; VEGF, vascular endothelial growth factor. upregulating the expression of NF-kB-dependent mole- ent immune responses: Th1 (IFNg and IL-12 dominant) cules MHC class II, CD80, and CD86 [19–22]. The cells mediate cellular immunity and activate macrophages, importance of NF-kB activation in immune response was and they are considered proinflammatory; Th2 (IL-4 and supported by the observations in knockout mice. Inactiva- IL-5 dominant) cells, which potentiate antiparasite and –/– –/– tion of RelB and NF-kB2 in relb and nfkb2 caused an humoral immunity, and inhibit macrophage activation, are impairment of APC function. The loss of NF-kB1 and c-Rel considered anti-inflammatory. As NF-kB controls the –/– –/– in nfkb1 and rel mice resulted in multiple defects in expression of Th1 cytokines IL-2, IFNg, and IL-12, activa- the activation of T and B cells, and weakened responses tion of NF-kB should facilitate Th1 subset development. to pathogens [23]. Indeed, transgenic mice expressing, in the T lineage, an inhibitor of NF-kB (a nondegradable mutant of IkBa, also NF-k kB facilitates T helper 1 subset development called ‘super-repressor’ IkBa [srIkBa]), had weakened After activation, CD4 T helper (Th) cells can differentiate Th1 and enhanced Th2 responses [24,25]. T cells from into Th1 or Th2 effector subsets. These two types of cells transgenic mice expressing Rac2, an upstream NF-kB produce distinct profiles of cytokines and regulate differ- activator, accordingly developed Th1 type responses [26]. commentary review reports primary research Available online http://arthritis-research.com/content/3/4/200 NF-k kB and the perpetuation of chronic for proliferation, it causes cell death unless certain survival inflammation factors are provided. PDGF is one such factor that over- Secreted products of activated T cells and direct cell–cell comes the pro-apoptotic proclivity of c-Myc. We found contacts induce activation of macrophages, the major pro- that blocking NF-kB activation abrogated the protective ducers of inflammatory cytokines in RA synovium. NF-kB effect of PDGF, indicating that, in PDGF signaling, NF-kB controls the expression of cytokines IL-1b and TNFa, the transmits two signals: one is required for the induction of essential mediators of inflammation in RA. TNFa and IL-1 c-Myc; and the second is an anti-apoptotic signal that neu- are potent inducers of NF-kB activation, suggesting an tralizes c-Myc cytotoxicity, conceivably by inducing the interdependence of persistent NF-kB activation and sus- expression of a protective gene (or multiple genes) [32]. tained levels of IL-1 and TNFa. Indeed, expression of As c-Myc is heavily overexpressed in RA synovium, NF-kB srIkBa abrogated the induction of IL-1b and TNFa in activation may contribute to synovial hyperplasia by inhibit- human macrophages and primary FLS [14,27]. A recent ing c-Myc-induced apoptosis and promoting proliferation. study by Aupperle et al indicates that, in RA FLS, A point of interest is that the pathway via which PDGF IKKb/IKK-2 is the principal kinase in activation of NF-kB in induced NF-kB activation involved phosphatidylinositol 3- response to IL-1 and TNFa. Expression of a DN mutant kinase (PI(3)K) and protein kinase B/Akt (see later). As the form of IKK-2 inhibited cytokine-inducible activation of PI(3)K/Akt pathway has been implicated in the pathogene- NF-kB and abrogated synthesis of IL-6 and IL-8, as well sis of numerous human malignancies, this suggests that as expression of ICAM-1 and collagenase-1. In contrast, similar mechanisms may operate in the promotion of the DN IKKa/IKK-1 had no effect [28]. The notion that hyperplasia in RA and cancer. IKKb/IKK-2 is the key convergence pathway for cytokine- induced NF-kB activation is consistent with results of Apoptosis genetic studies in IKK knockout mice [5]. Many pro-apoptotic stimuli, including TNFa, radiation, and chemotherapy, induce NF-kB activation. NF-kB activation It is worthy of note that suppression of NF-kB inhibited delivers, in most cell types, an anti-apoptotic signal that expression of many proinflammatory molecules, including counteracts cell death. NF-kB suppression of apoptosis IL-1, TNFa, IL-6, IL-8, ICAM-1 and VCAM-1, but had little, appears to be a transcriptional event since it activates if any, effect on the expression of anti-inflammatory expression of anti-apoptotic genes TRAF1 and TRAF2, cytokines IL-10 and IL-1 receptor antagonist [14,29–31]. c-IAP1 and c-IAP2, the Bcl-2 homologs A1/Bfl-1 and Bcl- This suggests that NF-kB activation facilitates the xL, IEX-1, and XIAP (reviewed in [35]). In our studies, impaired balance of proinflammatory and anti-inflammatory blocking NF-kB activation in primary rat SCW FLS molecules in the arthritic joint. strongly potentiated the cytotoxicity of TNFa and FasL. Consistent with this, administration of distinct inhibitors of NF-k kB and hyperplasia NF-kB (proteasomal inhibitors and adenoviral gene trans- Normal synovium is a delicate tissue lining the joint fer of srIkBa) in vivo resulted in accelerated apoptosis in capsule but, in RA, the synovium transforms into an joints of rats with pristane-induced and SCW-induced aggressive, tumor-like structure called pannus, which arthritis [14]. These studies are in agreement with that invades and erodes the joint. Experimental evidence sug- published by Zhang et al, who observed that NF-kB acti- gests that NF-kB activation may facilitate synovial hyper- vation was required to protect RA FLS against the cytotox- plasia by promoting proliferation and inhibiting apoptosis icity of TNFa in a human RA/SCID mouse model, of RA FLS. presumably through induction of anti-apoptotic protein XIAP [36]. These findings indicate an important role for Proliferation NF-kB in protecting FLS against apoptosis in RA syn- NF-kB serves as a positive regulator of cell growth in ovium, conceivably by inhibiting the cytotoxicity of TNFa myoblasts and fibroblasts by inducing the expression of and FasL. Because TNFa is a potent mitogen in RA FLS, c-Myc and cyclin D1, proteins required for cell cycle pro- NF-kB appears as a master switch determining whether gression [32–34]. Our studies in primary rat FLS have TNFa exerts mitogenic or pro-apoptotic effects. shown that stimulation with platelet-derived growth factor (PDGF) and basic fibroblast growth factor induced NF-kB Recent work from our laboratory and by other workers has, activation, which was required for induction of c-Myc and as already mentioned, established NF-kB as a target of the DNA synthesis [32] (J Romashkova, S Makarov, unpub- PI(3)/Akt pathway that has a prominent role in cell survival lished observations). In contrast, the mitogenic activity of and proliferation in cancer. The PI(3)K/Akt pathway has insulin-like growth factor-1, which did not activate NF-kB, been shown to mediate activation of NF-kB in response to was not influenced by NF-kB inhibitors (J Romashkova, S a wide variety of stimuli, including PDGF [32], TNFa [37], Makarov, unpublished observations). Another function of IL-1 [38], bradykinin [39], and oncogenic H-Ras [40] and NF-kB in mitogenic signaling in FLS is to protect cells Her-2/neu [41]. Akt-dependent NF-kB activation has been against cytotoxicity of c-Myc. Although c-Myc is required shown to mediate anti-apoptotic functions of PDGF [32] Arthritis Research Vol 3 No 4 Makarov and Her-2/neu [41], and to inhibit cell death induced by cytokines IL-1a and IL-1b, TNFa, IL-6, and IL-17 [53,54]. deregulated c-myc [32], H-Ras [40], and TNFa [41]. Pre- The contacts with activated T cells and osteoblast/stromal cisely how Akt activates NF-kB-dependent transcription is cells expressing high levels of TRANCE/RANKL/ODF a matter of debate. Several groups, including that of the promote osteoclast maturation and induce bone resorbing present author, demonstrated an involvement of IKK, thus activity, while administration of osteoprotegrin, a soluble implicating IkB-dependent mechanisms [32,37,39,41,42], decoy receptor for RANKL, prevents osteoclast differenti- while results by other workers demonstrate IkB-indepen- ation and precludes bone loss in animal arthritis [20,55]. dent mechanisms, in which Akt potentiates the transcrip- The critical importance of NF-kB in bone turnover was tional function of NF-kB [38,40]. It is possible that the underscored by the observations in double-knockout –/– –/– mechanisms connecting Akt with NF-kB, as well as the nfkb1 nfkb2 mice that develop osteopetrosis owing to contribution of NF-kB pathway in the anti-apoptotic func- accumulation of immature osteoclasts [56]. tion of Akt, are cell type and stimulus specific. A role for Akt in the pathogenesis of RA and the contribution of Akt The NF-k kB pathway as a therapeutic target to NF-kB activation in RA synovium are not known, but Many conventional anti-inflammatory and anti-rheumatic there is circumstantial evidence that this link may exist. drugs, including glucocorticoids, aspirin, sodium salicy- The activity of the PI(3)K/Akt pathway is negatively regu- late, sulfosalazine, and gold compounds, are inhibitors of lated by the phosphatase PTEN, a tumor suppressor fre- NF-kB activation. The list of therapeutics that inhibit quently inactivated in human malignancies [43] and in NF-kB also includes numerous natural and synthetic some autoimmune diseases, such as Cowden disease antioxidants, immunosuppressants, and natural plant com- and Sjögren’s syndrome [44]. The importance of the pounds, suggesting that the ability to suppress NF-kB PTEN-PI(3)K/Akt connection in autoimmune disease was activation at least partially accounts for their therapeutic +/– demonstrated by observations in PTEN heterozygous effects [57]. This interpretation, however, is complicated mice that exhibited defects in Fas-induced apoptosis and by the fact that most of the conventional drugs are not developed autoimmune disease [45], and in PI(3)K trans- very potent inhibitors of NF-kB, and that they can also genic mice that developed strikingly similar pathology affect other signaling pathways. More clear answers were [46]. Although PTEN mutations were not found in RA, the obtained using animals with genetically inactivated NF-kB –/– expression of PTEN is strikingly reduced in RA synovial signaling. Inactivation of c-Rel and NF-kB1 in rel and –/– lining [47], suggesting that deregulated PTEN may result nfkb1 knockout mice rendered the animals refractory to in activation of the PI(3)K/Akt pathway and contribute to development of CIA [58]. Transgenic mice expressing activation of NF-kB. The role of Akt and the Akt–NF-kB srIkBa in the T lineage were similarly refractory to CIA connection in RA clearly merits further investigation. [25]. These genetic studies are in a good agreement with the experiments that utilized highly specific inhibitors of NF-k kB and tissue remodeling NF-kB. In our studies, liposomal delivery of NF-kB decoys FLS are considered the major effectors of RA joint (double-stranded oligonucleotides containing NF-kB destruction. Inflammatory milieu in the RA joint results in a binding sites) effectively prevented the recurrence of highly invasive phenotype of RA FLS. Several lines of evi- SCW arthritis in rats. Intriguingly, the suppression of dence suggest that NF-kB activation contributes to the arthritis was evident not only in the ipsilateral, treated destructive potential of RA FLS. First, NF-kB mediates joints, but also in the contralateral, untreated joints, indi- transcriptional activation of several matrix metallopro- cating systemic effects of local anti-NF-kB therapy [14]. teinases (MMP). The promoter of MMP-1 has a NF-kB Administration of NF-kB decoys in a similar study signifi- binding site that is required for the induction of MMP-1 by cantly reduced the severity of CIA in rats, and inhibited the IL-1b [48]. Furthermore, NF-kB activation was found nec- production of IL-1 and TNFa within the joints [59]. In a essary for the induction of MMP-3, MMP-9, and MMP-13 study by Palombella et al, a proteasomal inhibitor of IkB expression [49–51]. Second, NF-kB activation is neces- degradation afforded protection against SCW-induced sary for the induction of cyclooxygenase-2 and inducible arthritis in rat [15]. Together, these animal studies strongly nitric oxide synthetase, the enzymes that catalyze synthe- support the feasibility of using NF-kB inhibitors in RA. sis of proinflammatory prostaglandins and nitric oxide metabolites [7]. Finally, NF-kB activation is required for the The prospects of anti-NF-k kB therapy for RA induction of vascular endothelial growth factor, an The efficacy of anti-NF-kB therapy in animal models of RA endothelial cell-specific mitogen and a pivotal regulator of allows for optimism, but many questions remain to be angiogenesis in RA [52]. answered. First, future therapeutic applications will require development of specific and potent inhibitors of the NF-kB Osteoclast is another cell type in which NF-kB activation pathway. Second, the safety of a long-term use of specific may have a prominent role in RA joint destruction. Bone NF-kB inhibitors remains to be elucidated. The lessons marrow-derived osteoclast precursors are recruited to RA from genetic studies revealed that basal NF-kB activity is synovium by elevated levels of NF-kB-dependent required for normal development, particularly for protection commentary review reports primary research Available online http://arthritis-research.com/content/3/4/200 of liver against apoptosis, and that inactivation of the NF- 12. Miyazawa K, Mori A, Yamamoto K, Okudaira H: Constitutive tran- scription of the human interleukin-6 gene by rheumatoid syn- kB pathway may be associated with detrimental side oviocytes: spontaneous activation of NF-kappa B and CBF1. effects (reviewed in [23]). 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Journal

Arthritis Research & Therapy – Springer Journals

Published: Jun 1, 2001

Keywords: Rheumatology; Orthopedics

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