Protein Kinase C θ Plays a Fundamental Role in Different Types of Chronic Colitis

Kiyotaka Nagahama, Atsuhiro Ogawa, Katsunori Shirane, Yasuyo Shimomura, Ken Sugimoto, Atsushi Mizoguchi

Research output: Contribution to journalArticle

29 Citations (Scopus)

Abstract

Background & Aims: Dysregulated host/microbial interactions induce the development of colitis by activating deleterious acquired immune responses. Activation of CD4+ T cells is mainly induced through signaling machinery associated with immunologic synapse (IS). A key molecule associated with the IS is protein kinase C (PKC) θ. However, the role of PKCθ in the pathogenesis of colitis has not fully been defined. Methods: The role of PKCθ for the acquired-immune responses involved in the development of different types of colitis (CD45RB model, T-cell receptor [TCR] α knockout [KO] mice and interleukin [IL]-2KO mice) was examined by generating double KO mice and by utilizing cell transfer approaches. Results: Adoptive transfer of PKCθ-deficient naïve CD4+ T cells failed to induce T helper cell (Th) 1-mediated colitis in the immune-deficient host (CD45RB model). Development of Th2-mediated colitis in TCRαKO mice was also inhibited by the absence of PKCθ. In IL-2KO mice, which develop colitis because of dysregulated T-cell homeostasis, deficiency of PKCθ in CD4+ T cells failed to induce the development of severe colitis. Interestingly, absence of PKCθ led to a remarkable decrease in the proliferation, but not apoptosis, of colonic memory CD4+ T cells. This impaired proliferation resulted in a marked decrease in the colonic CD4+ T cells that are capable of producing IL-17. In addition, deficiency of PKCθ inhibited the production of Th2 cytokines by colonic CD4+ T cells. Conclusions: PKCθ serves as a common and fundamental signaling molecule in the development of different types of colitis and may represent an attractive target for treating inflammatory bowel disease.

Original languageEnglish
Pages (from-to)459-469
Number of pages11
JournalGastroenterology
Volume134
Issue number2
DOIs
Publication statusPublished - 02-2008
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Hepatology
  • Gastroenterology

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