Interleukin-23 Promotes a Distinct CD4 T Cell Activation State Characterized by the Production of Interleukin-17

Abstract

Interleukin (IL)-17 is a pro-inflammatory cytokine that is produced by activated T cells. Despite increasing evidence that high levels of IL-17 are associated with several chronic inflammatory diseases including rheumatoid arthritis, psoriasis, and multiple sclerosis, the regulation of its expression is not well characterized. We observe that IL-17 production is increased in response to the recently described cytokine IL-23. We present evidence that murine IL-23, which is produced by activated dendritic cells, acts on memory T cells, resulting in elevated IL-17 secretion. IL-23 also induced expression of the related cytokine IL-17F. IL-23 is a heterodimeric cytokine and shares a subunit, p40, with IL-12. In contrast to IL-23, IL-12 had only marginal effects on IL-17 production. These data suggest that during a secondary immune response, IL-23 can promote an activation state with features distinct from the well characterized Th1 and Th2 profiles. Interleukin (IL)1 -17 is a T cell-derived pro-inflammatory molecule that stimulates epithelial, endothelial, and fibroblastic cells to produce other inflammatory cytokines and chemokines including IL-6, IL-8, G-CSF, and MCP-1 (1-8). IL-17 also synergizes with other cytokines including tumor necrosis factor-␣ and IL-1␤ to further induce chemokine expression (7, 9). Interleukin-17 levels are found to be significantly increased in rheumatoid arthritis synovium (10, 11), during allograft rejection (12-15), and in other chronic inflammatory diseases including multiple sclerosis (16) and psoriasis (17)(18)(19). Although clearly produced by activated T cells, previous reports have not provided clear classification of IL-17 within the paradigm of Th1 and Th2 polarized cytokine profiles.We have examined the possibility that IL-17 is expressed in response to signals distinct from those associated with the Th1 or Th2 response. We observe a previously unrecognized activity of the recently identified cytokine . IL-23 is a heterodimeric cytokine that shares one subunit, p40, with IL-12. The initial characterization of this cytokine has suggested it can promote proliferation within the memory T cell population. Subsequent work demonstrated that transgenic over-expression of the second component of IL-23, p19, was sufficient to induce systemic inflammation and premature death (21). In addition, the mice had markedly elevated levels of circulating neutrophils. Interestingly they did not exhibit consistent elevation of IFN-␥, a hallmark effect of IL-12. These data suggest that IL-23 may have a biological role substantially distinct from that of IL-12. In this report we present evidence that IL-23 acts to induce a distinct T cell activation state that produces IL-17 as a principle effector cytokine. EXPERIMENTAL PROCEDURESCell Culture-Single cell suspensions of spleen were prepared from C57/BL-6 mice, and mononuclear cells were isolated from suspended splenocytes by density gradient centrifugation. 2 ϫ 10 6 cells/ml were cultured with IL-2 (100 units/ml) in the presence or absence of vario...

TLR2‐activated human langerhans cells promote Th17 polarization via IL‐1β, TGF‐β and IL‐23

“…Therefore, we hypothesized a role of TLR2-expressing LC for polarizing Th17 immune responses and investigated their potential to induce IL-17. In this study we show that peptidoglycan (PGN)-stimulated MoLC secreted IL-6, IL-1b, IL-23, and TGF-b Blocking of TLR2 by specific antibody inhibited IL-6, IL- To date, IL-6 and TGF-b are prominent cytokine candidates for polarization of naive Th cells into Th17 cells, whereas IL-23 is discussed for Th17 outgrowth of already differentiated cells [5][6][7]26]. In human skin, among other cytokines IL-6 is produced by LC upon microbial stimulation by PGN and other TLR2 agonists [23].…”

Complement C5a regulates IL‐17 by affecting the crosstalk between DC and γδ T cells in CLP‐induced sepsis

“…Th cells producing IL-17 (Th17 cells) are a distinct subset of effector cells that differentiate from naive T cells in response to IL-6 and TGF-b [25,26], whereas IL-23 serves as an important factor to expand previously differentiated Th17 cell populations and gd T cells [27,28]. Our data showed that C5a significantly increased IL-17 production by T lymphocytes in the presence of DC, while it had no influence on IL-17 production from T lymphocyte when DC were absent.…”

Regulation of the development of acute hepatitis by IL‐23 through IL‐22 and IL‐17 production

“…Since IL-23 regulates the production of both IL-22 [4] and IL-17 [3], we further examined the effect of exogenous IL-23 on susceptibility to Con A-induced hepatitis. In WT mice, exogenous IL-23 significantly increased the serum levels of both IL-22 and IL-17 as expected (Fig.…”

“…IL-23 acts on memory-type cells [2] and induces the production of IL-17 [3] and IL-22 [4]. Moreover, IL-23 is an essential factor in the survival and expansion of Th17 cells [5], which produce cytokines including IL-17, IL-17F, IL-22, IL-6 and TNF-a [6].…”

“…However, IL-6-deficient mice were reported to have no impairment in IL-22 expression during Con A-induced hepatitis [24]. IL-23 also has the ability to induce the production of IL-22 [4] and IL-17 [3]. In addition, there are conflicting reports as to the role of IL-17 in Con A-induced hepatitis and the susceptibility of IL-17-deficient mice to hepatitis [24,31].…”