TY - JOUR
T1 - Protein Kinase C θ Plays a Fundamental Role in Different Types of Chronic Colitis
AU - Nagahama, Kiyotaka
AU - Ogawa, Atsuhiro
AU - Shirane, Katsunori
AU - Shimomura, Yasuyo
AU - Sugimoto, Ken
AU - Mizoguchi, Atsushi
N1 - Copyright:
Copyright 2018 Elsevier B.V., All rights reserved.
PY - 2008/2
Y1 - 2008/2
N2 - 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.
AB - 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.
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U2 - 10.1053/j.gastro.2007.11.005
DO - 10.1053/j.gastro.2007.11.005
M3 - Article
C2 - 18155708
AN - SCOPUS:38649118188
SN - 0016-5085
VL - 134
SP - 459
EP - 469
JO - Gastroenterology
JF - Gastroenterology
IS - 2
ER -