No abstract

Thymus and activation-regulated chemokine (TARC)/CCL17 and macrophage-derived chemokine (MDC)/CCL22 are a pair of CC chemokines known to selectively attract T(h)2 type memory T cells via CCR4. Here we examined circulating levels of TARC and MDC in patients with atopic dermatitis (AD) and control subjects by using plasma samples, which reflect blood contents of chemokines more accurately than serum samples. The plasma levels of TARC and MDC were significantly elevated in AD patients. These values also strongly correlated with disease severity and serum lactate dehydrogenase levels, and weakly correlated with serum total IgE levels and blood eosinophilia. Previous studies demonstrated TARC immunoreactivity in the epidermal layer of AD lesional skin and production of TARC by a human keratinocytic cell line HaCaT upon stimulation with IFN-gamma. Here we demonstrated MDC immunoreactivity in the epidermal layer of AD skin at levels stronger than that of TARC. Furthermore, primary epidermal keratinocytes expressed both TARC and MDC mRNA upon stimulation with IFN-gamma, but efficiently secreted only MDC. These results suggest a post-transcriptional regulation in TARC production. IFN-gamma also induced TARC and MDC mRNA in mouse skin. Collectively, both TARC and MDC play important roles in the local accumulation of T(h)2 cells in AD lesional skin. Production of T(h)2-attracting chemokines by epidermal keratinocytes upon treatment with IFN-gamma, which is also the potent inducer of T(h)1-attracting chemokines, may underline the pivotal role of IFN-gamma in the chronic phase of AD where both T(h)1 and T(h)2 responses are mixed.

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All fungi use multiple mitogen-activated protein kinase (MAPK) cascades to respond to external signals to regulate specialized responses. In this study, we cloned and characterized a putative MAPKKK gene ChSte11, orthologous to yeast STE11, of Cochliobolus heterostrophus. DeltaChste11 strains showed defects in conidiation, sexual development, melanization and the formation of appressoria. These mutants were significantly less virulent on corn plants than the wild type. Similar phenotypes were observed in mutants of Chk1-MAPK, a putative downstream protein kinase of ChSte11. These results suggested that ChSte11 regulates various morphological changes and pathogenicity via Chk1 MAPK. Both DeltaChste11 and Deltachk1 strains showed severe sensitivity to oxidative stress, hydrogen peroxide, and heavy metals, cupric or ferric cations. DeltaBmhog1 strains, mutants of the HOG1-type MAPK, did not show sensitivity to these forms of stress. Our results strongly suggested that the Ste11-type MAPKKK regulates not only various morphological changes and pathogenicity, but also adaptations to stress via Chk1-type MAPK in filamentous fungi.

Significance GATA-binding protein 3 (Gata3) controls the differentiation of naive CD4 T cells into T helper 2 (Th2) cells by induction of chromatin remodeling at the Th2 cytokine gene loci. Gata3 also facilitates Th2 cell proliferation via unknown mechanisms. We have identified a functional Gata3/RuvB-like protein 2 (Ruvbl2) complex that regulates the proliferation of differentiating Th2 cells through the repression of a CDK inhibitor, cyclin-dependent kinase inhibitor 2c ( Cdkn2c ). Gata3 directly bound to the Cdkn2c locus in an Ruvbl2-dependent manner, and Cdkn2c-knockdown experiments indicated an important role for this molecule in the Gata3-mediated induction of Th2-cell proliferation. Ruvbl2-knockdown Th2 cells showed decreased antigen-induced expansion and caused less airway inflammation in vivo, indicating an important role for Ruvbl2 in Th2 cells in allergic reactions.