Biology of IL-27 and its role in the host immunity against Mycobacterium tuberculosis

Abstract

IL-27, a heterodimeric cytokine of IL-12 family, regulates both innate and adaptive immunity largely via Jak-Stat signaling. IL-27 can induce IFN-γ and inflammatory mediators from T lymphocytes and innate immune cells. IL-27 has unique anti-inflammatory properties via both Tr1 cells dependent and independent mechanisms. Here the role and biology of IL-27 in innate and adaptive immunity are summarized, with special interest with immunity against Mycobacterium tuberculosis.

Keywords: IL-12 family; IL-27; IL-27Rα; Immunity; Mycobacterium tuberculosis.

Figure 1

Signaling involved in IL-27 expression. IL-27 is largely produced by Antigen-presenting cells (APCs) such as Dendritic cells (DCs) and macrophages upon stimulation with TLRs agonists, IFN-α, IFN-γ or microbial infections. It consists of two subunits (p28/EBI3) which are expressed independently. TLR2, TLR4 and TLR9-associated MyD88 can induce EBI3 expression through the binding of NF-𝛋B subunits (p50/p65) and PU.1 to the EBI3 promoter. TLR4-associated MyD88 induces p28 expression through binding of NF-𝛋B-c-Rel and AP-1/c-Fos to the p28 promoter, TLR4-associated TRIF induces p28 expression by binding of IRF3 to the p28 promoter. The IFN-α and IFN-γ induces p28 expression through the binding of IRF3 and IRF8 to the p28 promoter, respectively. In addition, IFN-γ-mediated IL-27 instead of IL-27p28 gene expression is positively regulated by the C-Jun N-terminal kinases (JNK), mitogen-activated protein kinases (MAPKs) and the phosphoinositide 3-kinase (PI3K).

Figure 2

Regulatory role of IL-27 in the immune response against Mycobacterium tuberculosis. (A) IL-27 induced by Mtb infection modulates macrophage response. IL-27 inhibits autophagy by inducing negative regulator factors of autophagy mTOR and Mcl-1 through PI3K/AKT and PI3K, respectively. IL-27 induces IL-10 production through Stat1/Stat3, which in turn blocks phagosomal maturation. It also suppresses TNF-α and IL-12 via Stat3 and both cytokines required for augmenting IFN-γ production by macrophages. In addition, IL-27 targeting NF-kB to inhibit IL-18 mediated IFN-γ production. Suppression of IFN-γ led to down-regulation of V-ATPase and CD63 and Capethsin D (CD) and subsequently suppression of phagosomal acidification. (B) IL-27 induced IL-10-producing type 1 regulatory T cells (Tr1) cell via Stat1/Stat3 and AhR/c-Maf pathway, which in turn suppress Th1 and Th17 cells. IL-27 directly inhibits Th17 cells by inhibiting ROR-γ expression and IL-6 signaling.

Figure 2

Regulatory role of IL-27 in the immune response against Mycobacterium tuberculosis. (A) IL-27 induced by Mtb infection modulates macrophage response. IL-27 inhibits autophagy by inducing negative regulator factors of autophagy mTOR and Mcl-1 through PI3K/AKT and PI3K, respectively. IL-27 induces IL-10 production through Stat1/Stat3, which in turn blocks phagosomal maturation. It also suppresses TNF-α and IL-12 via Stat3 and both cytokines required for augmenting IFN-γ production by macrophages. In addition, IL-27 targeting NF-kB to inhibit IL-18 mediated IFN-γ production. Suppression of IFN-γ led to down-regulation of V-ATPase and CD63 and Capethsin D (CD) and subsequently suppression of phagosomal acidification. (B) IL-27 induced IL-10-producing type 1 regulatory T cells (Tr1) cell via Stat1/Stat3 and AhR/c-Maf pathway, which in turn suppress Th1 and Th17 cells. IL-27 directly inhibits Th17 cells by inhibiting ROR-γ expression and IL-6 signaling.