Control of T helper 2 cell function and allergic airway inflammation by PKCζ

Abstract

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. PKC has been implicated in the regulation of apoptosis and NF-B, as well as in the control of T-dependent responses, although no defects were detected in naïve T cells from PKC ؊/؊ mice. Here, we report that PKC is critical for IL-4 signaling and Th2 differentiation. Thus, PKC levels are increased during Th2 differentiation, but not Th1 differentiation, of CD4 ؉ T cells, and the loss of PKC 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, PKC ؊/؊ mice display dramatic inhibition of ovalbumin-induced allergic airway disease, strongly suggesting that PKC can be a therapeutic target in asthma.apoptosis ͉ asthma ͉ NF-B

Loss of PKCλ/ι impairs Th2 establishment and allergic airway inflammation in vivo

“…For these reasons, we sought to determine whether PKC / is necessary for an optimal Th2 inflammatory response in vivo, although it does not seem to be necessary for Th2 differentiation driven by the exogenous addition of IL-4 under standard in vitro conditions. In this regard, it is well established that Th2 cells play a critical role in the development of allergic airway inflammation (11). Because our data show that PKC / is required for a proper balance of Th2/Th1 cytokines in vitro, we reasoned that PKC / might affect the airway allergy response in vivo.…”

“…The number of double-positive cells (CD4 ϩ CD8 ϩ ) and single-positive cells (CD4 ϩ or CD8 ϩ ) in the thymus also did not differ in conditional PKC / -deficient and wild-type mice (Table S2). Because PKC has been shown to play a critical role during Th2 differentiation (11), and because of the high homology between the 2 aPKCs, we sought to determine whether the conditional deletion of PKC / in activated T cells would produce an effect similar to that of PKC deficiency. To do so, we stimulated purified naïve CD4 ϩ T cells from mice of different genotypes with anti-CD3 in the absence or in the presence of anti-CD28; the levels of different secreted cytokines were detected by ELISA.…”

“…IL-4 and IL-13 share interactions with the IL-4 receptor chain and activate the transcription factor Stat6 through a Jak1/Jak3 signaling pathway (6,10). We recently have presented in vitro, ex vivo, and in vivo genetic evidence that the atypical PKC (aPKC) isoform, PKC , is necessary for optimal activation of the IL-4 signaling cascade upstream of Jak1 (11). Furthermore, in vivo adoptive transfer experiments using PKC Ϫ/Ϫ mice and cells demonstrated that PKC in Th2 cells is required for allergy-induced airway inflammation (11).…”

“…We recently have presented in vitro, ex vivo, and in vivo genetic evidence that the atypical PKC (aPKC) isoform, PKC , is necessary for optimal activation of the IL-4 signaling cascade upstream of Jak1 (11). Furthermore, in vivo adoptive transfer experiments using PKC Ϫ/Ϫ mice and cells demonstrated that PKC in Th2 cells is required for allergy-induced airway inflammation (11). These findings established PKC as an important mediator of Th2 differentiation in vivo in the IL-4 signaling pathway.…”

Surfactant Protein A Activation of Atypical Protein Kinase C ζ in IκB-α-Dependent Anti-Inflammatory Immune Regulation

“…Alternatively, the I B-␣ increase observed in PKC Ϫ/Ϫ AM could result from de novo transcription and might be referred to a compensatory increase of PKC / . However, Western blot analysis of lung extracts from wt and PKCdeficient mice for PKC and PKC / protein expression with specific Abs revealed that the level of PKC / is not affected by the loss of PKC (55), rendering the latter explanation unlikely. The LPS-mediated I B-␣ increase in PKC Ϫ/Ϫ AM was abolished by pretreatment of the cells with SP-A, proposing that SP-A not only fails to stabilize I B-␣, but provides a signal that triggers I B-␣ degradation, presumably by activating IKK in a PKC -independent way.…”