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Biomedical subjects

Bobby J Cherayil

Publications and source records attributed to Bobby J Cherayil.

4 recordsLinked to original sources
PubMed2004

Developmentally regulated IkappaB expression in intestinal epithelium and susceptibility to flagellin-induced inflammation.

Necrotizing enterocolitis is a devastating inflammatory condition of the intestine that occurs almost exclusively in premature newborns. Although its exact pathogenesis is unclear, we have postulated that it may result from a predisposition of the immature intestine to mount an unusually robust and damaging response to microbial infection. In support of this idea, we report that the IL-8 response of an immature human enterocyte cell line to bacterial infection was significantly higher than that of a mature enterocyte cell line. The response in both cell lines was flagellin-dependent. Corresponding to the difference in IL-8 production, the immature enterocytes expressed appreciably lower levels of specific IkappaB genes when compared with the mature enterocytes. Similar developmentally regulated differences in cytokine response and IkappaB expression were also seen in primary rat enterocytes, indicating that these observations were not peculiarities of the cell lines. Furthermore, when the level of IkappaBalpha expression was increased in the immature cell line by transfection, the flagellin-dependent IL-8 response was attenuated. Thus, we have demonstrated a previously undescribed developmental regulation of IkappaB expression in the intestine involved in modulating the IL-8 response to bacterial infection, which may contribute to the pathogenesis of age-specific inflammatory bowel diseases such as necrotizing enterocolitis.

Adult↗
PubMed2004

Cooperative interactions between flagellin and SopE2 in the epithelial interleukin-8 response to Salmonella enterica serovar typhimurium infection.

Flagellin is an important stimulus for epithelial interleukin-8 (IL-8) secretion because of its ability to activate Toll-like receptor 5 (TLR5). SopE2, a Salmonella guanine nucleotide exchange factor (GEF), is also involved in intestinal inflammation. To clarify the proinflammatory mechanisms of these proteins, we examined their effects on IL-8 secretion and intracellular signaling in T84 epithelial cells. A Salmonella strain lacking SopE2 (and its homolog SopE) induced lower levels of IL-8 than the wild type and exhibited reduced activation of mitogen-activated protein kinases (MAPKs). Overexpression of wild-type SopE2 in this strain restored MAPK activation and augmented IL-8 production, whereas a mutant lacking GEF activity failed to increase IL-8 expression. Additional effects on signaling were demonstrated in transient transfection experiments, in which SopE2 enhanced the ability of TRAF6, a signal transducer downstream of TLR5, to activate the NF-kappaB transcription factor in 293 cells. Flagellin was also found to be required for IL-8 induction in T84 cells. In its absence, the ability of SopE2 overexpression to increase IL-8 secretion was impaired. Part of this impairment was related to the decreased motility of the flagellin-deficient strain, but lack of flagellin also affected translocation of SopE2 into the infected cells. Our results indicate that flagellin and SopE2 interact functionally at multiple levels to increase IL-8 secretion by epithelial cells-flagellin facilitating the translocation of SopE2, and SopE2 enhancing signaling pathways activated by flagellin. These observations offer a mechanistic explanation for the involvement of these proteins in the pathogenesis of Salmonella-induced gastroenteritis.

Bacterial Proteins↗
PubMed2003

Role of Toll-like receptor 4 in macrophage activation and tolerance during Salmonella enterica serovar Typhimurium infection.

Toll-like receptors (TLRs) play an important role in the innate immune response, particularly in the initial interaction between the infecting microorganism and phagocytic cells, such as macrophages. We investigated the role of TLR4 during infection of primary murine peritoneal macrophages with Salmonella enterica serovar Typhimurium. We found that macrophages from the C3H/HeJ mouse strain, which carries a functionally inactive Tlr4 gene, exhibit marked impairment of tumor necrosis factor alpha (TNF-alpha) secretion in response to S. enterica serovar Typhimurium infection. However, activation of extracellular growth factor-regulated kinase and NF-kappa B signaling pathways was relatively unaffected, as was increased expression of TNF-alpha mRNA. Furthermore, macrophage tolerance, which is associated with increased expression of the NF-kappa B p50 and p52 subunits, was induced by S. enterica serovar Typhimurium even in the absence of functional TLR4. These results indicate that during infection of macrophages by S. enterica serovar Typhimurium, TLR4 signals are required at a posttranscriptional step to maximize secretion of TNF-alpha. Signals delivered by pattern recognition receptors other than TLR4 are sufficient for the increased expression of the TNF-alpha transcript and at least some genes associated with macrophage tolerance.

Animals↗