Characterization of interleukin-7 and interleukin-7 receptor in the pathogenesis of rheumatoid arthritis

IL-7 is a member of the IL-2/IL-15 family of cytokines which can be secreted or presented on stromal cells, epithelial cells, endothelial cells, fibroblasts and smooth muscle cells (1-4). It has been shown that rheumatoid arthritis (RA) patients have elevated levels of circulating IL-7 compared to normal individuals (5, 6). Additionally, an increased concentration of IL-7 has been detected in RA compared to osteoarthritis (OA) synovial fluid (7, 8). However, the cells responsible for producing IL-7 in circulation as well as in RA synovial fluid are unknown. IL-7, in concert with other growth factors, can contribute to the expansion of T cell precursors (9). Mature T cells are also modulated by IL-7, first by costimulation of T cells through cytokine production, second by promoting TH1 differentiation, and last by inhibiting programmed cell death through the proteins of the Bcl-2 family, thereby maintaining T cell homeostasis (10-13). Further, dendritic cell development, maturation and antigen presentation are partially controlled by IL-7 (14). It has been shown that RA synovial fluid macrophages activated with IL-7 differentiate into osteoclasts (15). IL-7 was also the most potent factor to induce differentiation of bone-resorbing cells compared to a panel of 16 cytokines (TNF-α, IL-1, 6 and 8 and others) and growth factors (GM-CSF and M-CSF and others) (15, 16). Consistently, IL-7-/- mice have a significant increase in bone mass due to reduced RANKL concentration (17). These results suggest that IL-7 plays an important role in bone resorption by inducing osteoclast differentiation as well as RANKL production. Co-culture of T cells and monocytes stimulated by IL-7 is associated with TNF-α production by monocytes (5, 6). However, IL-7 activated T cells or monocytes cultured separately fail to produce TNF-α. Interestingly, the same group of investigators have shown that RA patients who are responsive to anti-TNF-α therapy have significantly lower circulating IL-7 levels compared to anti-TNF-α nonresponders (6). In RA synovial tissue, IL-7R expression correlated with number of T cells and IL-7 expression level (18). Further, blockade of IL-7R in RA peripheral blood and synovial fluid significantly reduced endogenous IL-7 induced IFN-γ production (18) suggesting that IL-7 and IL-7R play an important role in RA pathology by activating T cells. Consistently, blockade of IL-7R ameliorates collagen induced arthritis (CIA) joint inflammation by reducing T cell trafficking and proinflammatory factors produced by macrophages such as TNF-α, IL-1β, IL-6 and MMPs (19). In this paper, we demonstrate that IL-7 and IL-7R are coexpressed on RA synovial tissue lining and sublining macrophages and endothelial cells thereby identifying novel target cells responsive to IL-7 activation. Further, IL-7 and IL-7R expression is greatly increased in RA synovial fluid and peripheral blood macrophages as well as in RA peripheral blood monocytes compared to normal cells. We also show that activation with TLR4 ligand, IL-1β, and TNF-α can modulate expression of IL-7 and IL-7R in RA peripheral blood in vitro differentiated macrophages. Both IL-7 and IL-7R expression are markedly higher in RA compared to normal fibroblasts, however, only expression of IL-7R is affected by lipopolysaccharide (LPS) and TNF-α stimulation in RA fibroblasts. In contrast, TLR4 ligation and TNF-α stimulation of human microvascular endothelial cells (HMVECs) can significantly induce expression of IL-7 and its receptor. Last, we demonstrate that IL-7 can exert its pathological role by activating macrophages and endothelial cells to produce pro-angiogenic factors such as IL-8 and Ang-1. Hence, therapy directed against IL-7R ligation may reduce leukocyte migration by inhibiting angiogenesis in RA.