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Jak3 expression and Stat3 activity in patients with rheumatoid arthritis and spondyloarthropathy
 
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Online publication date: 2010-09-21
 
 
Reumatologia 2010;48(4):237-246
 
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ABSTRACT
Introduction: The Jak/Stat pathway (Janus kinase/signal transducer and activator of transcription) is used by many cytokines, hormones and growth factors involved in cellular mechanisms of gene expression, cellular activation, proliferation, differentiation and apoptosis. Data suggest that Jak/Stat activity is significant in the pathogenesis of rheumatoid arthritis (RA).
Objectives: The objective was to evaluate the expression of Jak3 and the activity of Stat3 in synovial fluid cells (SFCs) and blood leucocytes (BLs) in patients with RA and spondyloarthropathy (Spa) and compare it with parameters of disease activity used in clinical practice. Moreover, the relations between Jak3 expression and Stat3 activity were evaluated.
Material and methods: Nineteen patients with RA and twenty two pa­tients with Spa (ankylosing spondylitis, psoriatic arthritis and undi­ffer­entiated spondyloarthropathy) were involved in the study. Healthy individuals (n = 23) were recruited as a control group. In all groups the expression of Jak3 and the activity of Stat3 were measured using the immunocytochemic method in BLs. In 11 RA patients and in 12 Spa patients an expression of Jak3 and an activity of Stat3 were measured in SFCs. In patients laboratory parameters describing the activity of illness were measured. The X-ray pictures of the joints were also taken.
Results: In RA and Spa group, the expression of Jak3 and the activity of Stat3 were higher comparing to healthy subjects. The expression of Jak3 and Stat3 activity were higher in SFCs than BLs. A positive correlation between SFCs Stat3 activity and CRP concentration was observed. There were no correlations between Jak3 expression and Stat3 activity.
Conclusions: The function of Jak3 and Stat3 is related to the immunologic process during the course a RA and Spa. It seems that blocking this function can be a therapeutic pathway in both groups of patients.
 
REFERENCES (30)
1.
Rich RR. Clinical immunology: Principles and practice, 3rd Edition. Mosby Elsevier 2008.  .
 
2.
Noguchi M, Yi H, Rosenblatt HM, et al. Interleukin-2 receptor gamma chain mutation results in X-linked severe combined immunodeficiency in humans. Cell 1993; 73: 147-157.  .
 
3.
Asao H, Okuyama C, Kumaki S, et al. Cutting edge: the common gamma-chain is an indispensable subunit of the IL-21 receptor complex. J Immunol 2001; 167: 1-5.  .
 
4.
Pellegrini S, Dusanter-Fourt I. The structure, regulation and function of the Janus kinases (JAKs) and the signal transducers and activators of transcription (STATs). Eur J Biochem 1997; 248: 615-633.  .
 
5.
Gurniak CB, Berg LJ. Murine JAK3 is preferentially expressed in hematopoietic tissues and lymphocyte precursor cells. Blood 1996; 87: 3151-3160. .
 
6.
Tortolani PJ, Lal BK, Riva A, et al. Regulation of JAK3 expression and activation in human B cells and B cell malignancies. J Immunol 1995; 155: 5220-5226. .
 
7.
Walker JG, Ahern MJ, Coleman M, et al. Expression of Jak3, STAT1, STAT4 and STAT6 in inflammatory arthritis: unique Jak3 and STAT4 expression in dendritic cells in seropositive rheumatoid arthritis. Ann Rheum Dis 2006; 65: 149-156. .
 
8.
Walker JG, Ahern MJ, Coleman M, et al. Changes in synovial tissue Jak-STAT expression in rheumatoid arthritis in response to successful DMARD treatment. Ann Rheum Dis 2006; 65: 1558-1564. .
 
9.
Walker JG, Ahern MJ, Coleman M, et al. Characterisation of a dendritic cell subset in synovial tissue which strongly expresses Jak/STAT transcription factors from patients with rheumatoid arthritis. Ann Rheum Dis 2007; 66: 992-999. .
 
10.
Macchi P, Villa A, Giliani S, et al. Mutations of Jak-3 gene in patients with autosomal severe combined immune deficiency (SCID). Nature 1995; 377: 65-68. .
 
11.
Russell SM, Tayebi N, Nakajima H, et al. Mutation of Jak3 in a patient with SCID: essential role of Jak3 in lymphoid development. Science 1995; 270: 797-800. .
 
12.
Cao X, Shores EW, Hu-Li J, et al. Defective lymphoid development in mice lacking expression of the common cytokine receptor gamma chain. Immunity 1995; 2: 223-238. .
 
13.
Suzuki K, Nakajima H, Saito Y, et al. Janus kinase 3 (Jak3) is essential for common cytokine receptor gamma chain (gamma(c))-dependent signaling: comparative analysis of gamma(c), Jak3, and gamma(c) and Jak3 double-deficient mice. Int Immunol 2000; 12: 123-132. .
 
14.
Wen R, Wang D, McKay C, et al. Jak3 selectively regulates bax and Bcl-2 expression to promote T-cell development. Mol Cell Biol 2001; 21: 678-689. .
 
15.
Milici A, Kudlacz E, Audoly L, et al. Cartilage preservation by inhibition of Janus kinase 3 in two rodent models of rheumatoid arthritis. Arthritis Res Ther 2008; 10: R14. .
 
16.
Kanik K, Fleischmann R, Cutolo M, et al. Phase 2b dose ranging monotherapy study of the oral jak inhibitor CP-690,550 (CP) or adalimumab (ADA) vs placebo (PBO) in patients (PTS) with active rheumatoid arthritis (RA) with an inadequate response to DMARDS. Ann Rheum Dis 2009; 68 (Suppl 3): abstract 123. .
 
17.
Pesu M, Laurence A, Kishore N, et al. Therapeutic targeting of Janus kinases. Immunol Rev 2008; 223: 132-142. .
 
18.
Levy DE, Lee CK. What does Stat3 do? J Clin Invest 2002; 109: 1143-1148. .
 
19.
Akira S. Functional roles of STAT family proteins: lessons from knockout mice. Stem Cells 1999; 17: 138-146. .
 
20.
Akira S. Roles of STAT3 defined by tissue-specific gene targeting. Oncogene 2000; 19: 2607-2611. .
 
21.
Debidda M, Wang L, Zang H, et al. A role of STAT3 in Rho GTPase-regulated cell migration and proliferation. J Biol Chem 2005; 280: 17275-17285. .
 
22.
Bromberg J. Stat proteins and oncogenesis. J Clin Invest 2002; 109: 1139-1142. .
 
23.
Ivanov VN, Bhoumik A, Krasilnikov M, et al. Cooperation between STAT3 and c-jun suppresses Fas transcription. Mol Cell 2001; 7: 517-528. .
 
24.
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. .
 
25.
Krause A, Scaletta N, Ji JD, Ivashkiv LB. Rheumatoid arthritis synoviocyte survival is dependent on Stat3. J Immunol 2002; 169: 6610-6616. .
 
26.
Lee CK, Raz R, Gimeno R, et al. STAT3 is a negative regulator of granulopoiesis but is not required for G-CSF-dependent differentiation. Immunity 2002; 17: 63-72. .
 
27.
Yao Z, Kanno Y, Kereny M, et al. Nonredundant roles for STAT5a/b in directly regulating Foxp3. Blood 2007; 109: 4368-4375. .
 
28.
Wang F, Sengupta TK, Zhong Z, Ivashkiv LB. Regulation of the balance of cytokine production and the signal transducer and activator of transcription (STAT) transcription factor activity by cytokines and inflammatory synovial fluids. J Exp Med 1995; 182: 1825-1831. .
 
29.
Ernst M, Inglese M, Waring P, et al. Defective gp130-mediated signal transducer and activator of transcription (STAT) signaling results in degenerative joint disease, gastrointestinal ulceration, and failure of uterine implantation. J Exp Med 2001; 194: 189-203. .
 
30.
Ulfgren AK, Gröndal L, Lindblad S, et al. Interindividual and intra-articular variation of proinflammatory cytokines in patients with rheumatoid arthritis: potential implications for treatment. Ann Rheum Dis 2000; 59: 439-447.
 
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