Control of T helper 2 cell function and allergic airway inflammation by PKCzeta.
Asthma is a disease of chronic airway inflammation in which T helper (Th) 2 cells play a critical role. The molecular mechanisms controlling Th2 differentiation and function are of paramount importance in biology and immunology. PKCzeta has been implicated in the regulation of apoptosis and NF-kappaB, as well as in the control of T-dependent responses, although no defects were detected in naïve T cells from PKCzeta-/- mice. Here, we report that PKCzeta is critical for IL-4 signaling and Th2 differentiation. Thus, PKCzeta levels are increased during Th2 differentiation, but not Th1 differentiation, of CD4+ T cells, and the loss of PKCzeta impairs the secretion of Th2 cytokines in vitro and in vivo, as well as the nuclear translocation and tyrosine phosphorylation of Stat6 and Jak1 activation, essential downstream targets of IL-4 signaling. Moreover, PKCzeta-/- mice display dramatic inhibition of ovalbumin-induced allergic airway disease, strongly suggesting that PKCzeta can be a therapeutic target in asthma.
Centro de Biología Molecular Severo Ochoa and Departamento de Inmunologia y Oncologia-Centro Nacional de Biotecnología, Consejo Superior de Investigaciones Cientificas, Universidad Autonoma de Madrid, Cantoblanco, 28049 Madrid, Spain.
Pilar
P
Martin
Ricardo
R
Villares
Sandra
S
Rodriguez-Mascarenhas
Angel
A
Zaballos
Michael
M
Leitges
Judit
J
Kovac
Irene
I
Sizing
Paul
P
Rennert
Gabriel
G
Márquez
Carlos
C
Martínez-A
María T
MT
Diaz-Meco
Jorge
J
Moscat
D000818:Animals; D001249:Asthma / Q000276:immunology / Q000503:physiopathology*; D016535:Bronchial Hyperreactivity / Q000139:chemically induced / Q000276:immunology*; D002454:Cell Differentiation / Q000502:physiology; D016207:Cytokines / Q000378:metabolism; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D007249:Inflammation / Q000276:immunology*; D015847:Interleukin-4 / Q000378:metabolism; D007527:Isoenzymes / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D010047:Ovalbumin / Q000633:toxicity; D011493:Protein Kinase C / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology*; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism / Q000502:physiology*
D016207:Cytokines; D007527:Isoenzymes; D015847:Interleukin-4; D010047:Ovalbumin; D011493:Protein Kinase C