1. Academic Validation
  2. Differential regulation of IL-23 production in M1 macrophages by TIR8/SIGIRR through TLR4- or TLR7/8-mediated signaling

Differential regulation of IL-23 production in M1 macrophages by TIR8/SIGIRR through TLR4- or TLR7/8-mediated signaling

  • Cytokine. 2017 Nov;99:310-315. doi: 10.1016/j.cyto.2017.08.014.
Rui Yamaguchi 1 Arisa Sakamoto 2 Takatoshi Yamamoto 2 Shinji Narahara 2 Hiroyuki Sugiuchi 2 Yasuo Yamaguchi 3
Affiliations

Affiliations

  • 1 Graduate School of Medical Science, Kumamoto Health Science University, Kitaku Izumi-machi 325, Kumamoto 861-5598, Japan; Graduate School of Medical Science, Kumamoto University School of Medicine, Chuo-ku Honjo 1-1-1, Kumamoto 860-8556, Japan.
  • 2 Graduate School of Medical Science, Kumamoto Health Science University, Kitaku Izumi-machi 325, Kumamoto 861-5598, Japan.
  • 3 Graduate School of Medical Science, Kumamoto Health Science University, Kitaku Izumi-machi 325, Kumamoto 861-5598, Japan. Electronic address: yamaguti@kumamoto-hsu.ac.jp.
Abstract

Cross-talks between toll-like receptors (TLRs) including various negative regulatory mechanisms are many unknown. We investigated the differential mechanism of IL-23 production in M1 macrophages by single immunoglobulin interleukin-1 receptor-related (SIGIRR) molecule through TLR4 or TLR7/8. IL-12p40 production by M1 macrophages pretreated with human neutrophil Elastase (HNE) was synergistically enhanced IL-12p40, but not IL-23 production, after exposure to lipopolysaccharide (LPS). LPS (a TLR4 Agonist) induced a slight increase of IL-23 production, while Resiquimod (a TLR7/8 agonist) significantly enhanced IL-23 production. Expression of SIGIRR protein, a negative regulator of TLR4, was higher in M1 macrophages than in monocytes. Interestingly, SIGIRR siRNA induced a slight increment of IL-23 production after exposure of macrophages to LPS, while IL-23 production in response to Resiquimod was significantly upregulated by SIGIRR siRNA. Silencing SIGIRR enhanced IRF4 protein level determined by western blotting or ELISA. IRF4 siRNA dramatically restored IL-23 production after exposure to Resiquimod in macrophages transfected with SIGIRR siRNA. In conclusion, production of IL-23 is differentially regulated in M1 macrophages by SIGIRR through TLR4- or TLR7/8-mediated signaling. SIGIRR is both a negative regulator of TLR4 and a positive regulator of TLR7/8.

Keywords

Granulocyte–macrophage colony-stimulating factor; IL-12p40; IL-23; Interferon regulatory factor 5; Single immunoglobulin interleukin-1 receptor-related molecule.

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