Upregulation of Stromal Cell–Derived Factor By IL‐17 and IL‐18 Via a Phosphatidylinositol 3‐Kinase‐Dependent Pathway

Abstract

Th17 cells that produce interleukin (IL)‐17 play a key role in the pathogenesis of autoimmune inflammation. Among the various cytokines that are involved in the IL‐17 pathway, members of the IL‐1β family, including IL‐18, have recently gained attention. In this study, we stimulated synovial fibroblasts with a combination of IL‐17 and IL‐18 and quantified their stromal cell–derived factor‐1 (SDF‐1) production by enzyme‐linked immunosorbent assay and their transcript levels by reverse transcription–polymerase chain reaction. Both IL‐17 and IL‐18 significantly increased the level of SDF‐1, not only individually but also synergistically (P < 0.05). The synergism was effectively suppressed by anti‐IL‐17 and ‐IL‐18 antibodies, and a PI3K inhibitor. To the best of our knowledge, this is the first report of PI3K‐dependent synergism between IL‐18 and IL‐17, and this work adds a novel perspective of the role of IL‐18 in immune regulation. The individual effects of these two cytokines, and their interactions, suggest an interrelationship between the IL‐1 family and IL‐17.

IL-17 Promotes Differentiation of Splenic LSK− Lymphoid Progenitors into B Cells followingPlasmodium yoeliiInfection

“…Previous data suggest that IL-17 has a potential role in regulating protein production from stromal cells (11, 13–16). Therefore, gene expression for a number of hematopoietic growth factors and additional proteins that are produced by stromal cell populations in the LN (11, 14–16) were examined in stromal cells from P. yoelii infected WT and Il-17ra −/− mice.…”

“…Therefore, gene expression for a number of hematopoietic growth factors and additional proteins that are produced by stromal cell populations in the LN (11, 14–16) were examined in stromal cells from P. yoelii infected WT and Il-17ra −/− mice. Expression of Il-6 is significantly decreased in splenic stromal cells in the absence of IL-17R signaling, while Baff expression is unaltered (Figure 5A).…”

“…Although the potential contribution of various other IL-17R expressing cells cannot be ruled out; expression and robust up-regulation of IL-17RA on stromal cells after P. yoelii 17X infection, coupled with their ability to act as feeder cells for HSPC differentiation makes them a strong candidate for contributing to LSK − cell differentiation. The impact of IL-17 on stromal cells, particularly in development and differentiation of B cells has been explored in many instances of infection (14), autoimmunity (12, 13, 15, 16) and tumor progression (56, 57). Various studies have indicated the pluripotent role of IL-17 in the induction of several chemokines and growth factors that play crucial parts in B cell development, suggesting an indirect relationship between IL-17 and B lymphopoiesis.…”

“…In recent years, several studies have suggested an association of the pro-inflammatory cytokine IL-17 with lymphoid tissue development (11–16). IL-17 was shown to induce stromal cells to produce CXCL12 (14–16), and this chemokine was subsequently shown to be important for the development of tertiary lymphoid tissue (11, 12, 14).…”

“…Also, IL-17 has been demonstrated to promote the formation of tertiary lymphoid tissues (TLTs) in such sites as the lung and brain, resulting in the accumulation of B cells, which form a follicle-like structure and T cells, which surround the B cells (11–14). The ability of IL-17 to promote TLT formation is due in part to its capacity to induce the production of CXCL12 by stromal cells (12–16). Based on its role in modulating stromal cells in non-lymphoid tissues, IL-17 may also actively influence the stromal cell compartment in the spleen to promote a niche for extramedullary lymphopoiesis.…”