Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:4.2.3.23 (GAS)
 957 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The vasoactive intestinal peptide (VIP) and the pituitary adenylate cyclase-activating polypeptide (PACAP), two immunomodulatory neuropeptides that affect both innate and acquired immunity, down-regulate IL-12 p40 and inducible NO synthase expression in LPS/IFN-gamma-stimulated macrophages. We showed previously that VIP/PACAP inhibit NF-kappaB nuclear translocation through the stabilization of IkappaB and reduce IFN regulatory factor-1 (IRF-1) binding to the regulatory elements found in the IL-12 p40 and inducible NO synthase promoters. In this paper we studied the molecular mechanisms involved in the VIP/PACAP regulation of IRF-1 transactivating activity. Our studies indicate that the inhibition in IRF-1 binding correlates with a reduction in IRF-1 protein and mRNA in IFN-gamma-treated Raw 264.7 macrophages. In agreement with the described Janus kinase (Jak)1/Jak2/STAT1/IRF-1 activation pathway, VIP/PACAP inhibit Jak1/Jak2, STAT1 phosphorylation, and the binding of STAT1 to the GAS sequence motif in the IRF-1 promoter. The effects of VIP/PACAP are mediated through the specific VIP/PACAP receptor-1 and the cAMP/protein kinase A (PKA) transduction pathway, but not through the induction of suppressor of cytokine signaling-1 or suppressor of cytokine signaling-3. Because IFN-gamma is a major stimulator of innate immune responses in vivo, the down-regulation of IFN-gamma-induced gene expression by VIP and PACAP could represent a significant element in the regulation of the inflammatory response by endogenous neuropeptides.
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PMID:Inhibition of IFN-gamma-induced janus kinase-1-STAT1 activation in macrophages by vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide. 1097 15

Earlier we have demonstrated that IL-12 p40 homodimer (p40(2)) induces the expression of inducible nitric oxide synthase (iNOS) in microglia. This study was undertaken to investigate underlying mechanisms required for IL-12 p40(2)- and IL-12 p70-induced expression of iNOS in microglia. IL-12 p40(2) alone induced the activation of both extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein kinase (MAPK). Interestingly, the ERK pathway coupled p40(2) to iNOS expression via C/EBP beta, but not NF-kappaB, whereas the p38 pathway relayed the signal from p40(2) to iNOS expression via both NF-kappaB and C/EBP beta. Furthermore, by using microglia from IL-12R beta 1 (-/-) and IL-12R beta 2 (-/-) mice or siRNA against IL-12R beta 1 and IL-12R beta 2, we demonstrate that p40(2) induced the expression of iNOS in microglia via IL-12R beta 1-(ERK+p38)-(NF-kappaB +C/EBP beta) pathway. In contrast, both IL-12R beta 1 and IL-12R beta 2 were involved for IL-12 p70-induced microglial expression of iNOS. Although IL-12R beta 1 coupled p70 to NF-kappaB and C/EBP beta, IL-12R beta 2 was responsible for p70-mediated activation of GAS. This study delineates a new role of IL-12R beta 1 and IL-12R beta 2 for the expression of iNOS and production of NO in microglia that may participate in the pathogenesis of neuroinflammatory diseases.
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PMID:IL-12 p40 homodimer, the so-called biologically inactive molecule, induces nitric oxide synthase in microglia via IL-12R beta 1. 1930 59