Search

How inflammatory stimuli signal to the nucleus to restrict inflammation is poorly understood. Protein inhibitor of activated STAT1 (PIAS1), a transcriptional regulator that possesses small ubiquitin-related modifier (SUMO) E3 ligase activity, inhibits immune responses by selectively blocking the binding of NF-kappaB and STAT1 to gene promoters. We report here that PIAS1 becomes rapidly phosphorylated on Ser90 residue in response to various inflammatory stimuli. Mutational studies indicate that Ser90 phosphorylation is required for PIAS1 to repress transcription. Upon TNF treatment, wild-type PIAS1, but not the Ser90A mutant, becomes rapidly associated with the promoters of NF-kappaB target genes. Furthermore, IKKalpha, but not IKKbeta, interacts with PIAS1 in vivo and mediates PIAS1 Ser90 phosphorylation, a process that requires the SUMO ligase activity of PIAS1. Our results identify a signaling pathway in which proinflammatory stimuli activate the IKKalpha-mediated sumoylation-dependent phosphorylation of PIAS1 for the immediate repression of inflammatory gene activation.

Leptin, one of the most important adipokines, is not only an energy regulator but also a regulator of innate immunity. Inflammation plays a key role in the tissue damage after intracerebral hemorrhage (ICH), and we sought to investigate whether leptin has a detrimental effect on ICH. After the injection of a high replacement dose (0.04 mg/kg) and two pharmacologic doses (4 and 8 mg/kg) of leptin, brain water contents increased significantly compared with that of control mice (P<0.05), which was confirmed when comparing the results with leptin-deficient ob/ob and wild-type (WT) mice (78.8%±0.6% versus 79.7%±0.6%, P<0.05). The number of Ox6-positive microglia/macrophages was increased in the leptin-injected group and decreased in ob/ob compared with WT mice. Among the candidate signal transducers, an increase in signal transduction and activator of transcription 3 (STAT3) levels was found after leptin injection. When we administered NSC74859, a specific inhibitor of phosphorylated STAT3 (pSTAT3), the water content became normalized. Activity of pSTAT3 was found mainly in Ox6-positive microglia/macrophages, but not in either neurons or astrocytes. We demonstrate that leptin plays a critical role in the secondary brain injury around a hematoma and is a novel mediator of the inflammation. This detrimental effect of leptin on ICH is mediated by the STAT3 signaling pathway in inflammatory cells. [ABSTRACT FROM AUTHOR]

The chronic low-grade inflammation in adipose tissue plays a causal role in obesity-induced insulin resistance and its associated pathophysiological consequences. In this study, we investigated the effects of extracts of Broussonetia papyrifera root bark (PRE) and its bioactive components on inflammation and insulin sensitivity. PRE inhibited TNF-α-induced NF-κB transcriptional activity in the NF-κB luciferase assay and pro-inflammatory genes' expression by blocking phosphorylation of IκB and NF-κB in 3T3-L1 adipocytes, which were mediated by activating AMPK. Ten-week-high fat diet (HFD)-fed C57BL6 male mice treated with PRE had improved glucose intolerance and decreased inflammation in adipose tissue, as indicated by reductions in NF-κB phosphorylation and pro-inflammatory genes' expression. Furthermore, PRE activated AMP-activated protein kinase (AMPK) and reduced lipogenic genes' expression in both adipose tissue and liver. Finally, we identified broussoflavonol B (BF) and kazinol J (KJ) as bioactive constituents to suppress pro-inflammatory responses via activating AMPK in 3T3-L1 adipocytes. Taken together, these results indicate the therapeutic potential of PRE, especially BF or KJ, in metabolic diseases such as obesity and type 2 diabetes. [ABSTRACT FROM AUTHOR]