HG-9-91-01 Attenuates Murine Experimental Colitis by Promoting Interleukin-10 Production in Colonic Macrophages Through the SIK/CRTC3 Pathway

Inflamm Bowel Dis. 2021 Oct 20;27(11):1821-1831. doi: 10.1093/ibd/izab072.

Abstract

Background: Interleukin-10 (IL-10) is a potent immunoregulatory cytokine that plays a pivotal role in maintaining mucosal immune homeostasis. As a novel synthetic inhibitor of salt-inducible kinases (SIKs), HG-9-91-01 can effectively enhance IL-10 secretion at the cellular level, but its in vivo immunoregulatory effects remain unclear. In this study, we investigated the effects and underlying mechanism of HG-9-91-01 in murine colitis models.

Methods: The anti-inflammatory effects of HG-9-91-01 were evaluated on 2, 4, 6-trinitrobenzene sulfonic acid (TNBS)-, dextran sulfate sodium-induced colitis mice, and IL-10 knockout chronic colitis mice. The in vivo effector cell of HG-9-91-01 was identified by fluorescence-activated cell sorting and quantitative real-time polymerase chain reaction. The underlying mechanism of HG-9-91-01 was investigated via overexpressing SIKs in ANA-1 macrophages and TNBS colitis mice.

Results: Treatment with HG-9-91-01 showed favorable anticolitis effects in both TNBS- and DSS-treated mice through significantly promoting IL-10 expression in colonic macrophages but failed to protect against IL-10 KO murine colitis. Further study indicated that HG-9-91-01 markedly enhanced the nuclear level of cAMP response element-binding protein (CREB)-regulated transcription coactivator 3 (CRTC3), whereas treatment with lentiviruses encoding SIK protein markedly decreased the nuclear CRTC3 level in HG-9-91-01-treated ANA-1 macrophages. In addition, intracolonic administration with lentiviruses encoding SIK protein significantly decreased the nuclear CRTC3 level in the lamina propria mononuclear cells and ended the anti-inflammatory activities of HG-9-91-01.

Conclusions: We found that HG-9-91-01 promoted the IL-10 expression of colonic macrophages and exhibited its anticolitis activity through the SIK/CRTC3 axis, and thus it may represent a promising strategy for inflammatory bowel disease therapy.

Keywords: HG-9-91-01; IL-10; SIK family; inflammatory bowel disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Colitis* / chemically induced
  • Colitis* / drug therapy
  • Cytokines
  • Dextran Sulfate
  • Disease Models, Animal
  • Interleukin-10* / immunology
  • Macrophages* / immunology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Phenylurea Compounds / pharmacology*
  • Protein Serine-Threonine Kinases / metabolism*
  • Pyrimidines / pharmacology*
  • Transcription Factors / metabolism*
  • Trinitrobenzenesulfonic Acid

Substances

  • CRTC3 protein, mouse
  • Cytokines
  • HG-9-91-01
  • Phenylurea Compounds
  • Pyrimidines
  • Transcription Factors
  • Interleukin-10
  • Trinitrobenzenesulfonic Acid
  • Dextran Sulfate
  • Protein Serine-Threonine Kinases