Gadd45α Regulates p38-Dependent Dendritic Cell Cytokine Production and Th1 Differentiation

Abstract

Gadd45α inhibits the activation of p38 by the T cell alternative pathway involving phosphorylation of p38 Tyr323. Given that T cell p38 may play a role in Th1 development, the response to Th-skewing Ags was analyzed in Gadd45α−/− mice. Despite constitutively increased p38 activity in Gadd45α−/− T cells, the Th1 immune response to Toxoplasma gondii Ag (STAg), was diminished. In contrast to T cells, dendritic cells (DC) lacked the alternative p38 activation pathway. Gadd45α−/− DCs responded to STAg with low levels of MAP kinase cascade-dependent p38 activation, IL-12 production, and CD40 expression. Wild-type T cells transferred into Gadd45α−/− recipients had a diminished Th1 response to STAg, whereas Gadd45α−/− T cells transferred into wild-type hosts behaved normally. Therefore, Gadd45α has tissue-specific and opposing functions on p38 activity, and Gadd45α-regulated p38 activation in DCs is a critical event in Th1 polarization in vivo.

Genetic disruption of p38α Tyr323 phosphorylation prevents T-cell receptor–mediated p38α activation and impairs interferon-γ production

“…These studies also suggest that the activation mechanism involves dimerization and subsequent trans autophosphorylation of Thr180. 38 TCR-induced phosphorylation of p38␣ and ␤ Tyr323 has been found in T cells but not in B cells, dendritic cells, fibroblasts, or keratinocytes, 17,[39][40][41] which is consistent with an obligatory role for ZAP70. Another factor implicated in the alternative pathway is that in TCR-activated cells the Dlgh1 scaffold protein seems to be necessary for bridging ZAP70 (and perhaps Lck) with p38 and subsequent phosphorylation of Tyr323.…”

Transcriptional profiles during the differentiation and maturation of monocyte-derived dendritic cells, analyzed using focused microarrays

“…2). The increase in GADD45A mRNA might be related to the Th1 polarization effects of LPS-and CD40L-stimulated DC [44,45], because GADD45A expressed in DC was recently demonstrated to be essential for Th1 cell development using a knock-out mouse model [18]. GADD45B can not only induce apoptosis under certain conditions, but can also protect some cell lines from apoptosis [43,46,47].…”

“…Then we treated the cells for two days with three stimuli, LPS, TNF-α and trimeric CD40L, in order to generate mature DC. At the same time, we developed focused microarrays printed with oligonucleotide probes for 120 genes encoding co-stimulatory molecules, chemokines, chemokine receptors, cytokines, cytokine receptors, TLRs, and several other molecules, since these molecules have been reported to be important for DC differentiation and function [16][17][18]. We used these focused microarrays to systematically analyze the kinetics of gene transcription during DC differentiation and maturation in response to different stimuli.…”

Lack of the T cell–specific alternative p38 activation pathway reduces autoimmunity and inflammation

“…10 Interestingly, Gadd45␣ also binds and activates MEKK4, an MAPKKK upstream of MKK3 and MKK6, 11 which explains the paradox that in non-T cells Gadd45␣ is a positive regulator of p38 kinase activity, and its absence results in decreased p38-dependent responses, such as IL-12 and CD40 expression in activated dendritic cells and reduced UV-induced apoptosis of keratinocytes. 12,13 The autoimmunity seen in Gadd45␣ Ϫ/Ϫ mice was presumed to be secondary to elevated T-cell p38 activity and hyperproliferation, but it was not possible to rule out other, uncharacterized, activities of Gadd45␣ in its pathogenesis.…”