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Byline: Vijendran. Pragasam, Biju. Vasudevan, Nikhil. Moorchung Introduction: Leprosy or Hansen's disease is a chronic debilitating disease caused by Mycobacterium leprae. Host genetics are believed to strongly influence the course [...]

Byline: Nitin. Yadav, Jyotirmoy. Banerjee, Manjari. Tripathi, P. Chandra, Aparna. Dixit Intracerebral Hemorrhage (ICH) refers to the bleeding in the intracranial vault, meninges, and also the brain parenchyma.[1] Microglia are [...]

Abstract: Objective: To investigate the role of angiopoietin-2 (Ang-2) in tumor necrosis factor-α (TNF-α) induced apoptosis of alveolar epithelium cells (AECs). Methods: TNF-α was used to induce human alveolar epithelial [...]

TNF-[alpha] is a proinflammatory cytokine and is an important mediator of maternal endothelial dysfunction leading to preeclampsia. In this study, we tested whether IL-10 protects against TNF-[alpha]-induced endothelial dysfunction in murine aorta. In in vitro experiments, aortic rings of C57BL/6 female mice were incubated in Dulbecco's modified Eagle's medium in the presence of either vehicle (distilled [H.sub.2]O), TNF-[alpha] (4 nmol/1), or recombinant mouse IL-10 (300 ng/ml) or in the presence of both TNF-[alpha] and IL-10 for 22 h at 37[degrees]C. In in vivo experiments C57BL6/IL-10 knockout female mice were treated with saline or TNF-[alpha] (220 ng x [kg.sup.-1] x [day.sup.-1]) for 14 days. Aortic rings were isolated from in vitro and in vivo experiments and mounted in a wire myograph (Danish Myotech) and stretched to a tension of 5 mN. Endothelium-dependent relaxation was assessed by constructing cumulative concentration-response curves to acetylcholine (ACh, 0.001-10 [micro]mol/l) during phenylephrine (10 [micro]mol/l)-induced contraction. As a result, overnight exposure of aortic rings to TNF-[alpha] resulted in significant blunted maximal relaxing responses ([E.sub.max]) to ACh compared with untreated rings (22 [+ or -] 4 vs. 82 [+ or -] 3%, respectively). IL-10 knockout mice treated with TNF-[alpha] showed significant impairment in ACh responses ([E.sub.max]) compared with C57BL/6 mice treated with TNF-[alpha] (51 [+ or -] 3 vs. 72 [+ or -] 3%, respectively). Western blot analysis showed that endothelial nitric oxide synthase (eNOS) expression was reduced by TNF-[alpha] in in vitro and in vivo experiments, whereas IL-10 restored the eNOS expression. In conclusion, the anti-inflammatory cytokine IL-10 prevents impairment in endothelium-dependent vasorelaxation caused by TNF-[alpha] by protecting eNOS expression. tumor necrosis factor-[alpha]; nuclear factor-[kappa]B doi: 10.1152/ajpheart.00763.2009.

The major short-chain fatty acid (SCFA) butyrate is produced in the colonic lumen by bacterial fermentation of dietary fiber. Butyrate serves as primary fuel for the colonocytes and also ameliorates mucosal inflammation. Disturbed energy homeostasis seen in inflamed mucosa of inflammatory bowel disease patients has been attributed to impaired absorption of butyrate. Since sodium-coupled monocarboxylate transporter 1 (SMCT1, SLC5A8) has recently been shown to play a role in [Na.sup.+]-coupled transport of monocarboxylates, including SCFA, such as luminal butyrate, we examined the effects of proinflammatory TNF-[alpha] on SMCT1 expression and function and potential anti-inflammatory role of probiotic Lactobacillus species in counteracting the TNF-[alpha] effects. Rat intestinal epithelial cell (IEC)-6 or human intestinal Caco-2 cells were treated with TNF-[alpha] in the presence or absence of Lactobacilli culture supernatants (CS). TNF-[alpha] treatments for 24 h dose-dependently inhibited SMCT1-mediated, [Na.sup.+]-dependent butyrate uptake and SMCT1 mRNA expression in IEC-6 cells and SMCT1 promoter activity in Caco-2 cells. CS of L. plantarum (LP) stimulated [Na.sup.+]-dependent butyrate uptake (2.5-fold, P < 0.05), SMCT1 mRNA expression, and promoter activity. Furthermore, preincubating the cells with LP-CS followed by coincubation with TNF-[alpha] significantly attenuated the inhibitory effects of TNF-[alpha] on SMCT1 function, expression, and promoter activity. In vivo, oral administration of live LP enhanced SMCT1 mRNA expression in the colonic and ileal tissues of C57BL/6 mice after 24 h. Efficacy of LP or their secreted soluble factors to stimulate SMCT1 expression and function and to counteract the inhibitory effects of TNF-[alpha] on butyrate absorption could have potential therapeutic value. intestinal epithelial cell-6; SLC5A8; short-chain fatty acid; inflammatory bowel disease doi: 10.1152/ajpgi.00279.2010.

Purpose To determine the clinical relevance of 13 reported common single-nucleotide polymorphisms (SNPs) of cytokine genes in patients with major trauma. Methods Thirteen SNPs in nine key cytokine genes were selected for association study in 308 patients with major trauma on the basis of previous functional or association data. An allele-specific oligonucleotide array was developed and used to genotype 308 patients with major trauma. The clinical relevance of the 13 SNPs was assessed by observation of cytokine production and outcome of trauma patients. Results Results from the allele-specific oligonucleotide array indicated that 8 [interleukin-1[beta] (IL-1[beta])/-1470, IL-1[beta]/-511, IL-1[beta]/-31, IL-4/-589, IL-6/-572, IL-8/-251, IL-10/-819, and tumor necrosis factor [alpha] (TNF[alpha])/-308] out of the 13 SNPs were associated with respective ex vivo cytokine production by peripheral leukocytes in response to lipopolysaccharide (LPS) stimulation at admission, or risk of development of sepsis or organ dysfunction in major trauma patients. Patients with more than four risk alleles of the eight SNPs had more than 50% sepsis morbidity and more severe organ dysfunction. Conclusions Polymorphisms of IL-1[beta]/-1470, IL-1[beta]/-511, IL-1[beta]/-31, IL-4/-589, IL-6/-572, IL-8/-251, IL-10/-819, and TNF[alpha]/-308 are susceptibility loci for the development of sepsis and organ dysfunction in major trauma patients., Author(s): Wei Gu [sup.1], Ling Zeng [sup.1], Jian Zhou [sup.2], Dong-po Jiang [sup.2], Lianyang Zhang [sup.2], Ding-yuan Du [sup.3], Ping Hu [sup.3], Kehong Chen [sup.1], Qin Liu [sup.1], Zheng-guo Wang [...]

Nephrin, a crucial component of the slit diaphragm, is downregulated in proteinuric glomerular diseases including glomerulonephritis. We previously reported that 1) expression of nephrin in cultured podocytes is reinforced by retinoic acid (RA) and 1,25-dihydroxyvitamin D3, 2) these effects are mediated by retinoic acid receptor (RAR) and vitamin D receptor (VDR), and 3) basal and inducible expression of nephrin is downregulated by TNF-[alpha]. In the present investigation, we identified that TNF-[alpha] selectively represses activity of RAR but not VDR. To elucidate mechanisms underlying this observation, we tested involvement of downstream targets for TNF-[alpha]: nuclear factor-[kappa]B (NF-[kappa]B), mitogen-activated protein (MAP) kinases, phosphatidylinositol 3-kinase (PI3K)-Akt, and cAMP-protein kinase A (PKA). TNF-[alpha] caused activation of NF-[kappa]B, MAP kinases, and PI3K-Akt in podocytes, whereas blockade of these molecules did not affect inhibition of RAR by TNF-[alpha]. In contrast, TNF-[alpha] depressed activity of cAMP-PKA, and blockade of PKA inhibited basal and RA-induced activation of RAR. Furthermore, activity of RAR was significantly upregulated by cAMP, and the suppressive effect of TNF-[alpha] on RAR was reversed by cAMP-elevating agents. These results suggest that l) expression of nephrin in podocytes is regulated by the cAMP-RAR pathway and 2) suppression of nephrin by TNF-[alpha] is caused, at least in part, through selective inhibition of this pathway. tumor necrosis factor-[alpha]; protein kinase A doi: 10.1152/ajprenal.00512.2009.

ABSTRACT Thalidomide is anti-inflammatory under some conditions, yet has been reported to up-regulate Th1 (T helper 1) immunity measured by increased IL-2 (Interleukin-2) and gamma interferon. The authors have assessed [...]

Eccentric contraction (EC) is known to elicit inflammation and damage in skeletal muscle. Proinflammatory cytokine TNF-[alpha] plays an important role in this pathogenesis, but the time course of its response to EC and the regulatory mechanisms involved are not clear. The purpose of the study is twofold: 1) to investigate the gene expression of TNF-[alpha] in rat muscle during and after an acute bout of downhill running and the associated oxidoreductive (redox) changes; and 2) to examine whether EC activates muscle ubiquitin-proteolytic pathway resulting in necrosis and oxidative damage. Female Sprague-Dawley rats (age 3 mo) were randomly divided into five groups (n = 6) that ran on treadmill at 25 m/min at - 10% grade for 1 h (group 1) or 2 h (group 2) and were killed immediately; ran for 2 h and killed at 6 h after exercise (group 3), ran for 2 h and killed at 24 h after exercise (group 4); and killed at rest as controls (group 5). TNF-[alpha] mRNA and protein content showed progressive increases in the deep portion of vastus lateralis (DVL) and gastrocnemius muscles during and after EC. These changes were accompanied by a progressive decrease of mitochondrial aconitase activity and NF-[kappa]B activation. After 2 h of exercise, elevated levels of serum TNF-[alpha], endotoxin, creatine kinase, and lipid peroxidation marker were evident and persisted through 24 h postexercise. At 24 h, there were marked increases in [H.sub.2][O.sub.2] concentration, myleoperoxidase activity, and endotoxin level, along with nuclear accumulation of p65, in both muscles, mRNA level of ubiquitin-conjugating enzymes ([E.sub.2])-14k was progressively upregulated during exercise and recovery, whereas the expression of the Toll-like receptor 4 (TLR4) in DVL was downregulated in both muscles. We conclude that prolonged EC induces TNF-[alpha] expression possibly due to NF-[kappa]B activation stimulated by increased reactive oxygen species generation and endotoxin release. These inflammatory and prooxidative responses may underlie the processes of muscle proteolysis and oxidative damage. inflammation; rat; reactive oxygen species; skeletal muscle; TNF-[alpha] doi:10.1152/ajpregu.00480.2009