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IL-17-producing T helper (Th17) cells have been implicated in the pathogenesis of many inflammatory and autoimmune diseases. Targeting the effector cytokines IL-17 and GM-CSF secreted by autoimmune Th17 cells has been shown to be effective for the treatment of the diseases. Understanding a molecular basis of Th17 differentiation and effector functions is therefore critical for the regulation of the pathogenicity of tissue Th17 cells in chronic inflammation. Here, we discuss the roles of proinflammatory cytokines and environmental stimuli in the control of Th17 differentiation and chronic tissue inflammation by pathogenic Th17 cells in humans and in mouse models of autoimmune diseases. We also highlight recent advances in the regulation of pathogenic Th17 cells by gut microbiota and immunometabolism in autoimmune arthritis. [ABSTRACT FROM AUTHOR]

Abstract: In a previous study, we showed that the Ca2+/calmodulin-dependent protein kinase IIδ (CaMKIIδ) activates the mouse Per1 (mPer1) promoter through a 5′-GAGGGG-3′ motif near exon1B. Here we use luciferase reporter gene assays to document additive activation of the mPer1 promoter by CaMKIIδ and mitogen-activated protein kinase (MAPK) pathways. Transfection of constitutively active MEKK markedly increased mPer1 promoter activity in NB2A cells. Experiments using MAPK inhibitors and dominant-negative c-Jun NH2-terminal kinase 1 (JNK1) showed that extracellular signal-regulated kinase (ERK) accounts for MEKK-induced mPer1 gene activation. We next defined the ERK-responsive region in the mPer1 promoter. A region from −1735 to −1721 was required for ERK-induced promoter activation. We also identified a CaMKII-responsive element near exon 1B. Although mutation of the CaMKII-responsive element has no effect on the ERK responsiveness, elimination of a GC-rich sequence downstream of the CaMKII-responsive region totally abolished ERK responsiveness. Finally, ERK-induced promoter activation was additively potentiated by co-transfection with active CaMKIIδ. These results suggest that additive activation by ERK and CaMKII, most likely as a result of photic stimulation in the suprachiasmatic nucleus, plays a critical role in activating the mPer1 gene promoter. [Copyright &y& Elsevier]

To investigate whether the third cytoplasmic loop and the C-terminal cytoplasmic tail of dopamine D2 receptor (D2R) are involved in extracellular signal-regulated kinase (ERK) acti- vation and subsequent regulation of transcription factors, we established NG108-15 cells stably expressing D2LR and D2SR deleted 40 amino acid residues in the third cytoplasmic loop (NGD2LR-3rd-dele and NGD2SR-3rd-dele) or the C-terminal cytoplasmic tail (NGD2LR-C-dele and NGD2SR-C-dele) and evaluated these receptors' functions using luci-ferase reporter gene assay. Immunocytochemical studies showed similar intracellular distributions of D2LR-3rd-dele and D2SR-3rd-dele to D2LR and D2SR, respectively. Quinpirole- induced inhibition of forskolin-induced cyclic AMP responsive element (CRE) activation was not affected by the deletion of 40 amino acid residues. However, nuclear factor-kappa B (NF-κB) activation by D2R-3rd-dele was largely attenuated compared to that by D2R. Similarly, ERK or serum-responsive element (SRE) activation by quinpirole treatment was totally abolished in NGD2R-3rd-dele cells. Moreover, D2R-C-dele was diffusely distributed or clustered in the cell bodies and lost the receptor functions. Taken together, the 40 amino acid residues in the third cytoplasmic loop are essential for the ERK activation but not for inhibition of adenylyl cyclase through Gi/o proteins. In addition, the C-terminal cytoplasmic tail is essential for membrane association of D2Rs to elicit the receptor functions. [ABSTRACT FROM AUTHOR]

Abstract The dopamine D[sub 2] receptor (D2R) is target for antipsychotic drugs and associated with several neuropsychiatric disorders. D2R has a long third cytoplasmic loop and a short carboxyl-terminal cytoplasmic tail. It exists as two alternatively spliced isoforms, termed D2LR and D2SR, which differ in the presence and absence, respectively, of a 29 amino acid insert in the third cytoplasmic loop. To evaluate the differential roles of the two D2R isoforms, we transfected both isoforms into NG108-15 cells and observed their subcellular localization by a confocal laser scanning light microscope. D2SR was predominantly localized at the plasma membrane, whereas D2LR was mostly retained in the perinuclear region around the Golgi apparatus. Using a yeast two hybrid system with a mouse brain cDNA library and coimmunoprecipitation assay, we found that heart-type fatty acid binding protein (H-FABP) interacts with D2LR but not with D2SR. H-FABP is a cytosolic protein involved in binding and transport of fatty acids. Overexpressed H-FABP and endogenous H-FABP were colocalized with the intracellular D2LR in NG108-15 cells. Furthermore, in the rat striatum, H-FABP was detected in the D2R-expressing neurons. From these results, H-FABP is associated with D2LR, and may thereby modulate the subcellular localization and function of D2LR. [ABSTRACT FROM AUTHOR]

To clarify the roles of the X-linked inhibitor of apoptosis protein (XIAP), we investigated the effects of XIAP overexpression on taxol-induced cell growth arrest and apoptosis in the prostate cancer cell line (LNCaP). After the transfection of XIAP cDNA into LNCaP cells, we established clonal cell lines that overexpressed XIAP and examined the taxol effects on growth and apoptosis by 2-(4-lodophenyl)-3-(4-nitrophenyl)-5-(2,4-disulfophenyl)-2H-tetrazolium, monosodium salt and flow cytometric analysis. The effects of XIAP overexpression on caspase-3 were examined by immunoblot analysis and activity assay. The interaction between XIAP and caspase-3 in LNCaP cells was examined by cotransfection with myc-XIAP and caspase-3-HA cDNAs followed by immunoprecipitation and immunoblot analysis. Large amounts of XIAP were expressed in the established cell lines. Although the growth rates were reduced in a dose- and time-dependent manner by taxol, these effects were significantly decreased in XIAP stably overexpressing cell lines. In addition, we found that taxol treatment induced the cleavage of pro-caspase-3, followed by apoptosis, and that the overexpression of XIAP inhibited apoptosis by attenuating the cleavage of pro-caspase-3 and caspase-3 activity. Interestingly, XIAP bound to pro-caspase-3 in LNCaP cells transiently cotransfected with myc-XIAP and caspase-3-HA cDNAs, and this interaction was inhibited by taxol treatment. These results suggest that the overexpression of XIAP inhibits taxol-induced apoptosis through the decrease of caspase-3 activity and inhibition of the processing of pro-caspase-3. [ABSTRACT FROM AUTHOR]

Unfortunately, an error occurred in the following passus of the article. The word "receptor" was missing in the sentence "Because T cells do not express GM-CSF receptor [41], GM-CSF affects non-T cells." [ABSTRACT FROM AUTHOR]