Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P05412 (c-Jun)
 11,453 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mitogen-activated protein (MAP) kinases have been implicated as important mediators of the inflammatory response. Here we report that c-Jun NH(2)-terminal kinase (JNK), extracellular signal-regulated kinase (ERK), and p38 MAP kinase activities are reprogrammed during the IL-6 induced macrophage-like differentiation of the murine myeloid M1 cell line. Moreover, p38 inhibition upregulates JNK and ERK activity in M1 cells and in thioglycollate-elicited peritoneal exudate macrophages. IL-6-induced M1 differentiation also induces expression of the anti-inflammatory cytokine IL-10, and p38 inhibition potentiates this increase in IL-10 expression in an ERK-dependent manner. Thus, we speculate that during inflammatory conditions in vivo macrophage p38 may regulate JNK and ERK activity and inhibit IL-10 expression. These data highlight the importance of p38 in the molecular mechanisms of macrophage function.
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PMID:Inhibition of the p38 pathway upregulates macrophage JNK and ERK activities, and the ERK, JNK, and p38 MAP kinase pathways are reprogrammed during differentiation of the murine myeloid M1 cell line. 1211 10

Paraoxonase 2 (PON2) is a member of the paraoxonases gene family. PON2 is ubiquitously present in cells, including macrophages, and it was shown to protect against cellular oxidative stress. The aim of the present study was to analyze mechanisms involved in PON2 expression during monocyte/macrophage differentiation. PON2 expression was analyzed in vitro in THP-1 cells differentiated with 1alpha,25-dihydroxyvitamin D3 and in vivo in mouse peritoneal macrophages (MPM) isolated at increasing time intervals after intraperitoneal thioglycollate injection. PON2 expression (mRNA and protein) and activity gradually increased during monocyte/macrophage differentiation, up to five fold and eight fold in vitro and in vivo, respectively. This effect was associated with a gradual increase in cellular superoxide anion production. Supplementation of vitamin E to Balb/C mice inhibited the reduced nicotinamide adenine dinuleotide phosphate (NADPH)-oxidase-dependent increase in cellular superoxide anion production by 50% and down-regulated PON2 mRNA expression and activity by 30 and 60%, respectively. Furthermore, PON2 expression was lower by nine fold in MPM isolated from P47(phox-/-) (inactive NADPH oxidase) mice, in comparison to MPM from control mice. PON2 expression was found to be regulated, at least in part, by the transcription factor AP-1, as suggested by decreased JDP2 (AP-1 repressor) protein expression in the nucleus and by decreased PON2 expression in the presence of a Jun N-terminal kinase inhibitor (SP600125). The present study demonstrates, for the first time, that PON2 expression increases in monocytes during their maturation into macrophage as a result of NADPH-oxidase activation, and this process is partly regulated by the transcription factor AP-1. PON2 stimulation may represent a compensatory mechanism against the increase in cellular superoxide anion production and atherogenesis.
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PMID:Paraoxonase 2 (PON2) expression is upregulated via a reduced-nicotinamide-adenine-dinucleotide-phosphate (NADPH)-oxidase-dependent mechanism during monocytes differentiation into macrophages. 1554 23

Prodigiosin was isolated from marine bacteria Hahella chejuensis which has been recently discovered from Marado, Cheju Island, Republic of Korea. Immunosuppressive properties have been reported for prodigiosin members such as undecylprodigiosin, metacycloprodigiosin, prodigiosin and its synthetic analogue PNU156804 (PNU). However, the effect of this agent on macrophage function has not been characterized in detail. In the present study, we examined the effects of prodigiosin on the production of inflammatory cytokines and nitric oxide (NO) in lipopolysaccharide (LPS)-activated murine macrophage. When thioglycollate-elicited macrophages pre-exposed to prodigiosin (1-100 ng/ml) were stimulated with LPS, pretreatment with prodigiosin resulted in the inhibition of NO production and inducible nitric oxide synthase (iNOS) protein and mRNA expression in a concentration-dependent manner. In contrast, the production of pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha), interleukin-1 (IL-1) and IL-6 was not altered. Inhibition of iNOS protein expression appears to be at the transcriptional level, since prodigiosin decreased LPS-induced NF-kappaB activity through preventing the degradation of IkBalpha, with significant inhibition achieved following pretreatment with prodigiosin. However, prodigiosin did not exert any effect on AP-1 activity. Prodigiosin blocked phosphorylation of p38 mitogen-activated protein kinase (MAPK) and c-Jun NH(2)-terminal kinase (JNK), but not that of extracellular signal-regulated kinase 1/2 (ERK 1/2). These results indicate that the inhibition of these signaling molecules expression was correlated with the reduced production of NO in macrophages. Taken together, the present data suggest that prodigiosin reduces NO production and iNOS expression by inhibiting LPS-triggered p38 MAPK and JNK phosphorylation and NF-kappaB activation, thereby implicating a mechanism by which prodigiosin may exert its immunosuppressive effects.
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PMID:Prodigiosin isolated from Hahella chejuensis suppresses lipopolysaccharide-induced NO production by inhibiting p38 MAPK, JNK and NF-kappaB activation in murine peritoneal macrophages. 1799 95

Adenosine is generated during tissue hypoxia and stress, which reduces inflammation by suppressing the activity of most immune cells. Among its various actions, adenosine suppresses the production of proinflammatory cytokines including tumor necrosis factor (TNF)-alpha, through the cAMP-elevating A(2A) adenosine receptor (AR) subtype. In this study, we examined the signaling mechanisms by which A(2A)AR activation inhibits TNF-alpha production in thioglycollate-elicited mouse peritoneal macrophages. Pretreating murine macrophages with the nonselective AR agonist adenosine-5'-N-ethylcarboxamide (NECA), the A(2A)AR agonist 2-[p-(2-carboxyethyl)phenethylamino]-5'-N-ethylcarboxamidoadenosine (CGS 21680), or the cAMP-elevating agent forskolin reduced TNF-alpha production in response to lipopolysaccharide (LPS) by greater than 60%. All of these agents increased cAMP production in macrophages and activated protein kinase A (PKA). However, we were surprised to find that treating macrophages with three different PKA inhibitors or small interfering RNA-mediated knockdown of the exchange protein activated by cAMP (Epac-1) failed to block the suppressive actions of NECA or forskolin on LPS-induced TNF-alpha release. Instead, okadaic acid was effective at low concentrations that selectively inhibit protein serine/threonine phosphatases. Subsequent studies showed that NECA and forskolin decreased LPS-induced steady-state TNF-alpha mRNA levels; this effect was due to a decreased rate of transcription based on assays examining the rate of generation of primary TNF-alpha transcripts. Treatment with NECA or forskolin did not interfere with LPS-induced translocation or DNA binding of the RelA/p65 subunit of nuclear factor-kappaB or phosphorylation of inhibitor of nuclear factor-kappaB-alpha, extracellular signal-regulated kinase 1/2, c-Jun NH(2)-terminal kinase, or p38 kinase. Our results suggest that AR activation inhibits LPS-induced TNF-alpha production by murine macrophages at the level of gene transcription through a unique cAMP-dependent, but PKA- and Epac-independent, signaling pathway involving protein phosphatase activity.
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PMID:Adenosine suppresses lipopolysaccharide-induced tumor necrosis factor-alpha production by murine macrophages through a protein kinase A- and exchange protein activated by cAMP-independent signaling pathway. 1974 80