Signal transduction in rheumatoid arthritis

Current Opinion in Rheumatology

Volumn 16, Issue 3, 2004, Pages 231-237

  Sweeney, Susan E ^a   Firestein, Gary S ^a  

^a UNIVERSITY OF CALIFORNIA   (United States)

Author keywords

Cytokine; Rheumatoid arthritis; Signal transduction

Indexed keywords

CYTOKINE; IMMUNOGLOBULIN ENHANCER BINDING PROTEIN; JANUS KINASE; MITOGEN ACTIVATED PROTEIN KINASE; MITOGEN ACTIVATED PROTEIN KINASE INHIBITOR; MITOGEN ACTIVATED PROTEIN KINASE P38;

CLINICAL TRIAL; DRUG EFFICACY; ENZYME ACTIVATION; GENE REPRESSION; GENETIC TRANSCRIPTION; HUMAN; NONHUMAN; PRIORITY JOURNAL; PROTEIN EXPRESSION; REVIEW; RHEUMATOID ARTHRITIS; SIGNAL TRANSDUCTION;

ARTHRITIS, RHEUMATOID; CYTOKINES; GENES, TUMOR SUPPRESSOR; HUMANS; MEMBRANE GLYCOPROTEINS; MITOGEN-ACTIVATED PROTEIN KINASES; PROTEIN-TYROSINE KINASES; RECEPTORS, CELL SURFACE; SIGNAL TRANSDUCTION; TOLL-LIKE RECEPTORS; TRANSCRIPTION FACTORS;

EID: 1942500129     PISSN: 10408711     EISSN: None     Source Type: Journal    
DOI: 10.1097/00002281-200405000-00011     Document Type: Review

References (54)

1. Johnson GL, Lapadat R: Mitogen-activated protein kinase pathways mediated by ERK, JNK, and p38 protein kinases. Science 2002, 298:1911-1912.
2. Fijen J, Zijlstra J, De Boer P, et al.: Suppression of the clinical and cytokine response to endotoxin by RWJ-67657, a p38 mitogen-activated protein-kinase inhibitor, in healthy human volunteers. Clin Exp Immunol 2001, 124:16-20.
3. Kotlyarov A, Neininger A, Schubert C, et al.: MAPKAP kinase 2 is essential for LPS-induced TNF-alpha biosynthesis. Nat Cell Biol 1999, 1:94-97.
4. Schett G, Tohidast-Akrad M, Smolen JS, et al.: Activation, differential localization, and regulation of the stress-activated protein kinases, extracellular signal-regulated kinase, c-JUN N-terminal kinase, and p38 mitogen-activated protein kinase, in synovial tissue and cells in rheumatoid arthritis. Arthritis Rheum 2000, 43:2501-2512.
5. Han Z, Boyle DL, Aupperle KR, et al.: Jun N-terminal kinase in rheumatoid arthritis. J Pharmacol Exp Ther 1999, 291:124-130.
6. Chabaud-Riou M, Firestein GS: Expression and activation of MKK3 and MKK6 in rheumatoid arthritis. Am J Pathol 2004, 164:177-184. The upstream kinases MKK3 and MKK6 are activated in RA synovium and regulate p38 MAPK activity in cultured FLS.
7. Badger A, Griswold D, Kapadia R, et al.: Disease-modifying activity of SB 242235, a selective inhibitor of p38 mitogen-activated protein kinase, in rat adjuvant-induced arthritis. Arthritis Rheum 2000, 43:175-183.
8. Pargellis C, Regan J: Inhibitors of p38 mitogen-activated protein kinase for the treatment of rheumatoid arthritis. Curr Opin Invest Drugs 2003, 4:566-571.
9. Nishikawa M, Myoui A, Tomita T, et al.: Prevention of the onset and progression of collagen-induced arthritis in rats by the potent p38 mitogen-activated protein kinase inhibitor FR167653. Arthritis Rheum 2003, 48:2670-2681. A potent p38 MAPK inhibitor prevents CIA and joint destruction in rats.
10. Han Z, Boyle D, Chang L, et al.: c-Jun N-terminal kinase is required for metalloproteinase expression and joint destruction in inflammatory arthritis. J Clin Invest 2001, 108:73-81.
11. Han Z, Chang L, Yamanishi Y, et al.: Joint damage and inflammation in c-Jun N-terminal kinase 2 knockout mice with passive murine collagen-induced arthritis. Arthritis Rheum 2002, 46:818-823.
12. Sundarrajan M, Boyle DL, Chabaud-Riou M, et al.: Expression of the MAPK kinases MKK-4 and MKK-7 in rheumatoid arthritis and their role as key regulators of JNK. Arthritis Rheum 2003, 48:2450-2460. Upstream kinases MKK4 and MKK7 form a signaling complex with JNK and are the primary kinases that regulate JNK activation in cultured FLS.
13. Hammaker DR, Boyle DL, Chabaud-Riou M, et al.: Regulation of JNK1 by MEKK2 and MAP kinase kinase kinases in rheumatoid arthritis. J Immunol. (in press). The MAP kinase kinase kinase MEKK2 is highly expressed in RA synovium and cultured FLS. In addition, MEKK2 forms a complex with MKK4, MKK7, and JNK to regulate c-Jun phosphorylation.
14. Lacey D, Sampey A, Mitchell R, et al.: Control of fibroblast-like synoviocyte proliferation by macrophage migration inhibitory factor. Arthritis Rheum 2003, 48:103-109. ERK inhibition decreases the effect of MIF on FLS proliferation.
15. Handel ML, McMorrow LB, Gravallese EM: Nuclear factor-kappa B in rheumatoid synovium: localization of p50 and p65. Arthritis Rheum 1995, 38:1762-1770.
16. Aupperle K, Bennett B, Han Z, et al.: NF-kappa B regulation by I kappa B kinase-2 in rheumatoid arthritis synoviocytes. J Immunol 2001, 166:2705-2711.
17. Tak PP, Gerlag DM, Aupperle KB, et al.: Inhibitor of nuclear factor kappaB kinase beta is a key regulator of synovial inflammation. Arthritis Rheum 2001, 44:1897.
18. Miagkov A, Kovalenko D, Brown C, et al.: NF-kappaB activation provides the potential link between inflammation and hyperplasia in the arthritic joint. Proc Natl Acad Sci U S A 1998, 95:13859-13864.
19. Andreakos E, Smith C, Kiriakidis S, et al.: Heterogeneous requirement of IkappaB kinase 2 for inflammatory cytokine and matrix metalloproteinase production in rheumatoid arthritis: implications for therapy. Arthritis Rheum 2003, 48:1901-1912. Differential regulation of NF-kB by IKK2 based on the cell type and the specific stimulus was demonstrated. TNF-α production by synovial tissue cells was dependent on IKK2.
20. Kishore N, Sommers C, Mathialagan S, et al.: A selective IKK-2 inhibitor blocks NF-kappa B-dependent gene expression in interleukin-1 beta-stimulated synovial fibroblasts. J Biol Chem 2003, 278:32861-32871. A selective IKK2 small molecule inhibitor blocks NF-kB activation in FLS.
21. McIntyre KW, Shuster DJ, Gillooly KM, et al.: A highly selective inhibitor of I kappa B kinase, BMS-345541, blocks both joint inflammation and destruction in collagen-induced arthritis in mice. Arthritis Rheum 2003, 48:2652-2659. An oral IKK inhibitor is effective in murine CIA as assessed by clinical and histologic endpoints.
22. Hammaker D, Sweeney SE, Firestein GS: Signal transduction networks in rheumatoid arthritis. Ann Rheum Dis 2003, 62(Suppl 2):ii86-ii89. A concise review of signal transduction in RA that also includes data on a selective IKK2 inhibitor in adjuvant arthritis. The compound blocked both clinical arthritis and joint destruction in the arthritic rats.
23. Sharma S, tenOever BR, Grandvaux N, et al.: Triggering the interferon antiviral response through an IKK-related pathway. Science 2003, 300:1148-1151. The IKK-related kinases IKKi and TBK-1, previously thought to function primarily as activators of NF-kB, were shown to serve as the key signaling kinases involved in phosphorylation of IRF-3 and -7 and IFN-β production.
24. Fitzgerald KA, McWhirter SM, Faia KL, et al.: IKKepsilon and TBK1 are essential components of the IRF3 signaling pathway. Nat Immunol 2003, 4:491-496. The IKK-related kinases IKKi and TBK-1 were shown to serve as the key components involved in virus-activated phosphorylation of IRF-3 and -7 and IFN-β and RANTES production.
25. Kravchenko VV, Mathison JC, Schwamborn K, et al.: IKKi/IKKepsilon plays a key role in integrating signals induced by pro-inflammatory stimuli. J Biol Chem 2003, 278:26612-26619. New signaling pathways regulated by IKKi were identified. The kinase serves to link NF-kB and C/EBP pathways in response to LPS stimulation.
26. Aupperle KR, Yamanishi Y, Bennett BL, et al.: Expression and regulation of inducible IkappaB kinase (IKK-i) in human fibroblast-like synoviocytes. Cell Immunol 2001, 214:54-59.
27. Grall F, Gu X, Tan L, et al.: Responses to the proinflammatory cytokines interleukin-1 and tumor necrosis factor alpha in cells derived from rheumatoid synovium and other joint tissues involve nuclear factor kappa B-mediated induction of the Ets transcription factor ESE-1. Arthritis Rheum 2003, 48:1249-1260.
28. Han M, Kim J, Park B, et al.: NF-kappaB-dependent lymphocyte hyperadhesiveness to synovial fibroblasts by hypoxia and reoxygenation: potential role in rheumatoid arthritis. J Leukoc Biol 2003, 73:525-529. An interesting study demonstrating the NF-kB is activated in cultured FLS in a model of ischemia-reperfusion injury.
29. Elliott S, Coon C, Hays E, et al.: Bcl-3 is an interleukin-1-responsive gene in chondrocytes and synovial fibroblasts that activates transcription of the matrix metalloproteinase 1 gene. Arthritis Rheum 2002, 46:3230-3239.
30. Muller-Ladner U, Judex M, Ballhorn W, et al.: Activation of the IL-4 STAT pathway in rheumatoid synovium. J Immunol 2000, 164:3894-3901.
31. Yokota A, Narazaki M, Shima Y, et al.: Preferential and persistent activation of the STAT1 pathway in rheumatoid synovial fluid cells. J Rheumatol 2001, 28:1952-1959.
32. Sengupta T, Chen A, Zhong Z, et al.: Activation of monocyte effector genes and STAT family transcription factors by inflammatory synovial fluid is independent of interferon gamma. J Exp Med 1995, 181:1015-1025.
33. van der Pouw Kraan T, van Gaalen F, Kasperkovitz P, et al.: Rheumatoid arthritis is a heterogeneous disease: evidence for differences in the activation of the STAT-1 pathway between rheumatoid tissues. Arthritis Rheum 2003, 48:2132-2145. Microarray analysis of synovial tissue demonstrated a pattern in some patients consistent with STAT1 activation.
34. Heinrich PC, Behrmann I, Haan S, et al.: Principles of interleukin (IL)-6-type cytokine signalling and its regulation. Biochem J 2003, 15(374(Pt 1)):1-20. This is a comprehensive review of IL-6 signal transduction mechanisms.
35. Shouda T, Yoshida T, Hanada T, et al.: Induction of the cytokine signal regulator SOCS3/CIS3 as a therapeutic strategy for treating inflammatory arthritis. J Clin Invest 2001, 108:1781-1788. Adenoviral delivery of dominant negative STAT3 or SOCS3 suppressed clinical and pathologic changes in an animal model of arthritis.
36. Egan PJ, Lawlor KE, Alexander WS, et al.: Suppressor of cytokine signaling-1 regulates acute inflammatory arthritis and T cell activation. J Clin Invest 2003, 111:915-924. SOCS1 regulates acute inflammatory antigen-induced arthritis and CD4 T cell activation, suggesting that SOCS1 activation may have utility in RA.
37. Naka T, Kishimoto T: Joint disease caused by defective gp130-mediated STAT signaling. Arthritis Res 2002, 4:154-156. In a murine model, a deleted STAT binding site in the gp130 subunit of the IL-6 receptor complex results in excessive response to IL-6, defective SOCS induction, and inflammatory joint disease.
38. Hu X, Herrero C, Li WP, et al.: Sensitization of IFN-gamma Jak-STAT signaling during macrophage activation. Nat Immunol 2002, 3:859-866. LPS stimulation of IFN-γ-primed macrophages enhances signaling in RA synovial cells through STAT1.
39. Yao Q, Wang S, Glorioso JC, et al.: Gene transfer of p53 to arthritic joints stimulates synovial apoptosis and inhibits inflammation. Mol Ther 2001, 3:901-910.
40. Yamanishi Y, Boyle DL, Pinkoski MJ, et al.: Regulation of joint destruction and inflammation by p53 in collagen-induced arthritis. Am J Pathol 2002, 160:123-130.
41. Sun Y, Cheung J, Martel-Pelletier J, et al.: Wild type and mutant p53 differentially regulate the gene expression of human collagenase-3 (hMMP-13). J Biol Chem 2000, 275:11327-11332.
42. Yamanishi Y, Boyle DL, Rosengren S, et al.: Regional analysis of p53 mutations in rheumatoid arthritis synovium. Proc Natl Acad Sci U S A 2002, 99:10025-10030.
43. Kuenzler P, Kuchen S, Rihoskova V, et al.: Induction of p16 at sites of cartilage invasion in the SCID mouse coimplantation model of rheumatoid arthritis. Arthritis Rheum 2003, 48:2069-2073. RA FLS that invade cartilage in the SCID mouse implant model express p53, which may contribute to the aggressive phenotype of FLS in RA.
44. Hudson JD, Shoaibi MA, Maestro R, et al.: A proinflammatory cytokine inhibits p53 tumor suppressor activity. J Exp Med 1999, 190:1375-1382.
45. Morand EF, Leech M, Weedon H, et al.: Macrophage migration inhibitory factor in rheumatoid arthritis: clinical correlations. Rheumatology (Oxford) 2002, 41:558-562. MIF is expressed in RA FLS and tissue, and the level of expression correlates with clinical disease activity.
46. Leech M, Lacey D, Xue JR, et al.: Regulation of p53 by macrophage migration inhibitory factor in inflammatory arthritis. Arthritis Rheum 2003, 48:1881-1889. MIF inhibits p53 expression in RA FLS, and suppression of p53 by MIF can exacerbate disease in animal models of arthritis.
47. Perlman H, Bradley K, Liu H, et al.: IL-6 and matrix metalloproteinase-1 are regulated by the cyclin-dependent kinase inhibitor p21 in synovial fibroblasts. J Immunol 2003, 170:838-845. Analysis of p21-deficient mice reveals increased levels of MMPs and IL-6, implicating a role for p21 in the pathogenesis of arthritis.
48. Hikasa M, Yamamoto E, Kawasaki H, et al.: p21waf1/cip1 is down-regulated in conjunction with up-regulation of c-Fos in the lymphocytes of rheumatoid arthritis patients. Biochem Biophys Res Commun 2003, 304:143-147. p21 and STAT1 suppression is associated with increased c-Fos expression in RA lymphocytes.
49. Taniguchi K, Kohsaka H, Inoue N, et al.: Induction of the p16INK4a senescence gene as a new therapeutic strategy for the treatment of rheumatoid arthritis. Nat Med 1999, 5:760-767.
50. Bradley K, Bickel E, Gorges L, et al.: Retinoblastoma suppresses matrix metalloproteinase 1, but not interleukin-6, through a p38-dependent pathway in RA synovial fibroblasts. Arthritis Rheum (in press). Expression of Rb is reduced in RA synovium, and restoration of Rb inhibits cell cycle progression and MMP-1 secretion. Arthritis Rheum 2004, 50:78-87.
51. Bradley K, Bickel E, Gorges L, et al.: Retinoblastoma suppresses matrix metalloproteinase 1, but not interleukin-6, through a p38-dependent pathway in RA synovial fibroblasts. Arthritis Rheum (in press). Expression of Rb is reduced in RA synovium, and restoration of Rb inhibits cell cycle progression and MMP-1 secretion. Arthritis Rheum 2004, 50:78-87.
52. Choe JY, Crain B, Wu SR, et al.: Interleukin 1 receptor dependence of serum transferred arthritis can be circumvented by toll-like receptor 4 signaling. J Exp Med 2003, 197:537-542. TLR4 and IL-1 signaling pathways converge through MyD88. In a passive model of arthritis, synovitis was decreased in mice lacking IL-1 receptors. However, suppressed arthritis could be overcome by coadministration of small amounts of LPS to bypass the lack of IL-1 signaling.
53. Kyburz D, Rethage J, Seibl R, et al.: Bacterial peptidoglycans but not CpG oligodeoxynucleotides activate synovial fibroblasts by toll-like receptor signaling. Arthritis Rheum 2003, 48:642-650. Proteoglycans act through TLR2 to enhance integrins, cytokines, and MMPs expression in RA FLS.
54. Seibl R, Birchler T, Loeliger S, et al.: Expression and regulation of Toll-like receptor 2 in rheumatoid arthritis synovium. Am J Pathol 2003, 162:1221-1227. IL-1 or TNF-α increases TLR expression in cultured FLS.