Elevated Serum and Synovial Fluid Levels of Interleukin-34 in Rheumatoid Arthritis: Possible Association with Disease Progression via Interleukin-17 Production

Abstract

To measure the levels of interleukin-34 (IL-34) in serum and synovial fluid (SF) of patients with rheumatoid arthritis (RA) and to evaluate the effect of recombination human (rh) IL-34 on IL-17 production by peripheral blood mononuclear cells (PBMC) in RA patients, the serum and SF levels of IL-34, and the production of IL-17 by rhIL-34-treated PBMC of RA patients were measured by enzyme-linked immunosorbent assay. We also tested the change of IL-34 level after tumor necrosis factor (TNF)-α blockade therapy in 30 RA patients. In contrast to almost no detectable IL-34 in osteoarthritis (OA) and healthy serum, IL-34 could be detected in 93 out of the 125 RA cases (74.4%). Sera IL-34 levels were significantly higher in RA patients compared with the controls and correlated with disease activity. IL-34 levels were higher in SF samples than in sera in 11 RA patients. The level of serum IL-34 decreased after anti-TNF treatment. In the presence of rhIL-34, stimulation of PBMC from RA patients resulted in increased production of IL-17. These findings suggest that IL-34 may play a role in the pathogenesis of RA.

Joint Destruction and Osteoporosis are Associated with Upregulation of IL34 and Cathepsin k Expression in Rheumatoid Arthritis. Clinical Trial with Anti TNF α Therapy

“…This was in accordance with Tian et al, who reported that the level of serum IL-34 decreased after anti-TNF treatment in RA patients [14]. TNF inhibitors delay appearance of bone erosion in RA Stepwise multiple linear regression analysis for ∆SHS.…”

“…Similarly further reduction in serum cathepsin k was found in good responders [3.75(3-5.5)] versus poor responders [5.25(3.18-10.12)] which reflected that impact of treatment response was variable on patients of the same group. It may be due to other contributing poor factors as RF positivity, age, gender and disease duration, as three of them were male and all were seropositive and their disease duration range (12)(13)(14)(15)(16)(17)(18)(19)(20) years which declare that pathogenesis of RA may differ from a patient to another (disease severity), as well as effect of treatment varied also from one to another patient and this explanation was previously established by many authors [52].…”

“…It also could promote osteoclastogenesis in vitro [13]. Tian et al, found that IL-34 expression could be induced by TNF-α and IL-1β which are pivotal cytokines in RA [14]. Studies have shown that administration of an antibody or inhibitor against the c-Fms selectively and completely blocks osteoclastogenesis and bone erosion induced by TNF−α.…”

CSF-1 Receptor Signaling in Myeloid Cells

“…However, circulating CSF-1 (Stanley 1979;Janowska-Wieczorek et al 1991) shows humoral regulation (Cecchini et al 1994;Pollard and Stanley 1996;Dai et al 2004). In contrast, IL-34 is not detectable in the circulation of healthy individuals (Hwang et al 2012;Tian et al 2013) and thus IL-34 actions are likely to be restricted to the local microenvironments in which they are expressed. Through their different spatiotemporal expression, the two ligands play complementary roles in regulating the development, maintenance, and activity of specific macrophage populations, Langerhans cells, neuronal progenitors (Wei et al 2010;Greter et al 2012;Nandi et al 2012;Wang et al 2012), as well as osteoclasts (Dai et al 2002) and Paneth cells (Huynh et al 2009) and the regulation of cells of the female reproductive tract (Wei et al 2010).…”

Interleukin-34: A Potential Diagnostic and Therapeutic Target for Rheumatoid Arthritis

“…Interestingly, elevated levels of IL-34 were also detected in early RA (disease duration ≤ 6 mos) 2 and a significant association was found between IL-34 expression and synovitis severity 6 . Of greatest interest, significant positive correlations were found between IL-34 levels, inflammation variables (such as erythrocyte sedimentation rate and C-reactive protein), antibodies production (such as RF and anti-CCP), and disease activity indexes (such as tender joint count and the Disease Activity Score at 28 joints) 7 . The proinflammatory cytokines play a dual role in the pathogenesis of RA that can promote inflammation and the destruction of bone.…”