Interleukin-23: as a drug target for autoimmune inflammatory diseases

Abstract

Interleukin-23 (IL-23) is a member of the IL-12 family of cytokines with pro-inflammatory properties. Its ability to potently enhance the expansion of T helper type 17 (Th17) cells indicates the responsibility for many of the inflammatory autoimmune responses. Emerging data demonstrate that IL-23 is a key participant in central regulation of the cellular mechanisms involved in inflammation. Both IL-23 and IL-17 form a new axis through Th17 cells, which has evolved in response to human diseases associated with immunoactivation and immunopathogeny, including bacterial or viral infections and chronic inflammation. Targeting of IL-23 or the IL-23 receptor or IL-23 axis is a potential therapeutic approach for autoimmune diseases including psoriasis, inflammatory bowel disease, rheumatoid arthritis and multiple sclerosis. The current review focuses on the immunobiology of IL-23 and summarizes the most recent findings on the role of IL-23 in the pre-clinical and ongoing clinical studies.

Figure 1

A schematic diagram of different components making up the interleukin-23 (IL-23) and IL-12 receptors and the common signal transduction and activator of transcription 4 (STAT4) activation pathway. IL-12 receptor β1 (IL-12Rβ1) and IL-12Rβ2 each consists of three fibronectin type III (yellow) domains and two cytokine receptor (green) domains with an additional immunoglobulin-like domain (blue) on the latter. IL-23R closely resembles IL-12Rβ2 but without the fibronectin type III domains.

Figure 2

T helper type 17 (Th17) cell differentiation. Following T-cell receptor activation, naive CD4 T cells may differentiate into either Th1 cells in the presence of interleukin-12 (IL-12), which up-regulates interferon-γ (IFN-γ) synthesis via signal transduction and activator of transcription 4 (STAT4) signalling, or Th2 cells in the presence of IL-4. This stimulates STAT1 activation and T-bet transcription factor expression, leading to a Th1 phenotype. Conversely, IL-4 activates STAT6 signalling, which induces GATA3 transcription factor expression and determines Th2 cell differentiation. The Th17 phenotype develops in response to IL-6, transforming growth factor-β (TGF-β) and IL-23 via STAT3 and Smads signalling and the up-regulation of the transcription factor retinoic acid-related orphan receptor RORγt (RORC2 in humans) expression. Interleukin-23 through its receptors induces tyrosine phosphorylation of Jak2 and Tyk2. Jak2 next phosphorylates all STATs. STAT3/STAT4 alone and STAT3 through RORγt enhance Th17 differentiation. TGF-β acting together with IL-6 up-regulates RORγt and induces Th17 differentiation. In addition, Th1 and Th2 cytokines potently inhibit Th17 differentiation. Conversely, TGF-β inhibits the Th1 and Th2 differentiation both by inhibiting the IFN-γ and IL-4 synthesis by effector Th1 and Th2 cells and by blocking the IFN-γ and IL-4 activity on naive T cells. APC, antigen-presenting cells; TLR, Toll-like receptor; TNF-α, tumour necrosis factor-α;