Protein kinase C theta plays a fundamental role in different types of chronic colitis.
OBJECTIVE
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) theta. However, the role of PKCtheta in the pathogenesis of colitis has not fully been defined.


METHODS
The role of PKCtheta for the acquired-immune responses involved in the development of different types of colitis (CD45RB model, T-cell receptor [TCR] alpha 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 PKCtheta-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 TCRalphaKO mice was also inhibited by the absence of PKCtheta. In IL-2KO mice, which develop colitis because of dysregulated T-cell homeostasis, deficiency of PKCtheta in CD4(+) T cells failed to induce the development of severe colitis. Interestingly, absence of PKCtheta 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 PKCtheta inhibited the production of Th2 cytokines by colonic CD4(+) T cells.


CONCLUSIONS
PKCtheta 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.
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation; D002908:Chronic Disease; D003092:Colitis / Q000235:genetics* / Q000503:physiopathology*; D003106:Colon / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D006706:Homeostasis / Q000502:physiology; D020381:Interleukin-17 / Q000378:metabolism; D007376:Interleukin-2 / Q000235:genetics* / Q000502:physiology; D007527:Isoenzymes / Q000235:genetics* / Q000502:physiology*; D017493:Leukocyte Common Antigens / Q000235:genetics* / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011493:Protein Kinase C / Q000235:genetics* / Q000502:physiology*; D000074121:Protein Kinase C-theta; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics* / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D018417:Th1 Cells / Q000378:metabolism / Q000473:pathology; D018418:Th2 Cells / Q000378:metabolism / Q000473:pathology
D020381:Interleukin-17; D007376:Interleukin-2; D007527:Isoenzymes; D016693:Receptors, Antigen, T-Cell, alpha-beta; C489593:Prkcq protein, mouse; D011493:Protein Kinase C; D000074121:Protein Kinase C-theta; D017493:Leukocyte Common Antigens