Tyk2-mediated homeostatic control by regulating the PGE<sub>2</sub>-PKA-IL-10 axis

Ryuta Muromoto; Kenji Oritani; Tadashi Matsuda; Ryuta Muromoto; Kenji Oritani; Tadashi Matsuda

doi:10.3934/Allergy.2021013

AIMS Allergy and Immunology

2021, Volume 5, Issue 3: 175-183. doi: 10.3934/Allergy.2021013

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Tyk2-mediated homeostatic control by regulating the PGE₂-PKA-IL-10 axis

1.
Department of Immunology, Graduate School of Pharmaceutical Sciences, Hokkaido University, Kita-ku Kita 12 Nishi 6, Sapporo 060-0812, Japan
2.
Department of Hematology, International University of Health and Welfare, 4-3 Kouzunomori, Narita, Chiba 286-8686, Japan

Received: 20 April 2021 Accepted: 20 June 2021 Published: 22 June 2021

Tyrosine kinase 2 (Tyk2), which associates with the receptors for type I interferon (IFN) and interleukins (IL)-6, IL-10, IL-12, and IL-23, is critical to mediate cytokine-induced signals. Tyk2 plays an essential role in the constitutive production of small amount of type I IFNs and in the promotion of differentiation from naïve T cells into Th1 or Th17 effector cells via IL-12- and IL-23-induced signals. Additionally, Tyk2-mediated signaling suppresses the in vivo production of IL-10, which is a strong anti-inflammatory cytokine. The elevated IL-10 production in the peritoneal cells of Tyk2-deficient mice are alleviated by treatment with either diclofenac, a cyclooxygenase inhibitor, or H-89, a protein kinase A inhibitor. Notably, significantly higher basal prostaglandin E₂ (PGE₂) production is observed in peritoneal cavity of Tyk2-deficient mice than that of wild-type mice. Phosphorylation of cAMP response element-binding protein, induced by P. acnes and PGE₂ addition, is upregulated in Tyk2-deficient macrophages. This indicates that higher IL-10 production in Tyk2-deficient mice is likely a result of the enhanced PGE₂-protein kinase A pathway. Thus, Tyk2-mediated signaling regulates multiple events during immune and/or inflammatory responses.
- Tyk2,
- cytokines,
- signal transduction,
- immune system,
- inflammation,
- PGE₂,
- PKA,
- IL-10,
- virus-induced diabetes
Citation: Ryuta Muromoto, Kenji Oritani, Tadashi Matsuda. Tyk2-mediated homeostatic control by regulating the PGE2-PKA-IL-10 axis[J]. AIMS Allergy and Immunology, 2021, 5(3): 175-183. doi: 10.3934/Allergy.2021013

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Abstract

Tyrosine kinase 2 (Tyk2), which associates with the receptors for type I interferon (IFN) and interleukins (IL)-6, IL-10, IL-12, and IL-23, is critical to mediate cytokine-induced signals. Tyk2 plays an essential role in the constitutive production of small amount of type I IFNs and in the promotion of differentiation from naïve T cells into Th1 or Th17 effector cells via IL-12- and IL-23-induced signals. Additionally, Tyk2-mediated signaling suppresses the in vivo production of IL-10, which is a strong anti-inflammatory cytokine. The elevated IL-10 production in the peritoneal cells of Tyk2-deficient mice are alleviated by treatment with either diclofenac, a cyclooxygenase inhibitor, or H-89, a protein kinase A inhibitor. Notably, significantly higher basal prostaglandin E₂ (PGE₂) production is observed in peritoneal cavity of Tyk2-deficient mice than that of wild-type mice. Phosphorylation of cAMP response element-binding protein, induced by P. acnes and PGE₂ addition, is upregulated in Tyk2-deficient macrophages. This indicates that higher IL-10 production in Tyk2-deficient mice is likely a result of the enhanced PGE₂-protein kinase A pathway. Thus, Tyk2-mediated signaling regulates multiple events during immune and/or inflammatory responses.

Acknowledgments

The authors thank Editage (www.editage.com) for English language editing. This study was supported in part by Grant-in-Aid for scientific research 19H03364 (T.M.) and 20K07010 (R. M.) from Ministry of Education, Culture, Sports, Science and Technology of Japan.

Conflict of interest

All authors declare no conflicts of interest in this paper.

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