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

28 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 - 01-01-2008
Externally publishedYes

Fingerprint

Colitis
Protein Kinase C
T-Lymphocytes
Interleukins
Knockout Mice
Synapses
Microbial Interactions
Th1 Cells
Interleukin-17
Adoptive Transfer
T-Cell Antigen Receptor
Inflammatory Bowel Diseases
Homeostasis
Apoptosis
Cytokines

All Science Journal Classification (ASJC) codes

  • Hepatology
  • Gastroenterology

Cite this

Nagahama, Kiyotaka ; Ogawa, Atsuhiro ; Shirane, Katsunori ; Shimomura, Yasuyo ; Sugimoto, Ken ; Mizoguchi, Atsushi. / Protein Kinase C θ Plays a Fundamental Role in Different Types of Chronic Colitis. In: Gastroenterology. 2008 ; Vol. 134, No. 2. pp. 459-469.
@article{7cc7352179ff48e4af6cb51f52900c1c,
title = "Protein Kinase C θ Plays a Fundamental Role in Different Types of Chronic Colitis",
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 na{\"i}ve 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.",
author = "Kiyotaka Nagahama and Atsuhiro Ogawa and Katsunori Shirane and Yasuyo Shimomura and Ken Sugimoto and Atsushi Mizoguchi",
year = "2008",
month = "1",
day = "1",
doi = "10.1053/j.gastro.2007.11.005",
language = "English",
volume = "134",
pages = "459--469",
journal = "Gastroenterology",
issn = "0016-5085",
publisher = "W.B. Saunders Ltd",
number = "2",

}

Nagahama, K, Ogawa, A, Shirane, K, Shimomura, Y, Sugimoto, K & Mizoguchi, A 2008, 'Protein Kinase C θ Plays a Fundamental Role in Different Types of Chronic Colitis', Gastroenterology, vol. 134, no. 2, pp. 459-469. https://doi.org/10.1053/j.gastro.2007.11.005

Protein Kinase C θ Plays a Fundamental Role in Different Types of Chronic Colitis. / Nagahama, Kiyotaka; Ogawa, Atsuhiro; Shirane, Katsunori; Shimomura, Yasuyo; Sugimoto, Ken; Mizoguchi, Atsushi.

In: Gastroenterology, Vol. 134, No. 2, 01.01.2008, p. 459-469.

Research output: Contribution to journalArticle

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

PY - 2008/1/1

Y1 - 2008/1/1

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.

UR - http://www.scopus.com/inward/record.url?scp=38649118188&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=38649118188&partnerID=8YFLogxK

U2 - 10.1053/j.gastro.2007.11.005

DO - 10.1053/j.gastro.2007.11.005

M3 - Article

VL - 134

SP - 459

EP - 469

JO - Gastroenterology

JF - Gastroenterology

SN - 0016-5085

IS - 2

ER -