Journal
PEDIATRIC RESEARCH
Volume 59, Issue 1, Pages 89-95Publisher
INT PEDIATRIC RESEARCH FOUNDATION, INC
DOI: 10.1203/01.pdr.0000195101.74184.e3
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Funding
- EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH &HUMAN DEVELOPMENT [R37HD012437] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [P30DK040561, P01DK033506, R01DK070260] Funding Source: NIH RePORTER
- NICHD NIH HHS [R37 HD12437, R37 HD012437] Funding Source: Medline
- NIDDK NIH HHS [R01 DK070260, P30 DK040561-10, P30 DK40561, P30 DK040561, R01 DK70260, P01 DK033506, P01 DK33506] Funding Source: Medline
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Intestinal epithelial cells (IEC) are constantly exposed to bacterial components, such as LPS, without triggering proinflammatory immune responses.. This study demonstrates that chronic exposure of human-derived IEC to LPS induces tolerance to an endogenous inflammatory cytokine (1L-1 beta) activated IL-8 response that Occurs independently of TLR-4/MD-2 signaling. IL-8 production in response to activation by unrelated TNF-alpha and PMA signaling pathways is also inhibited, indicating a broad-spanning tolerance. Quantitative rtPCR and IL-8 promoter-luciferase assays demonstrate that tolerance is regulated at the transcriptional level and occurs independently of IEC cytodifferentiation. By contrast, LPS does not significantly alter other proinflammatory signaling cascades in IEC that function independently of IL-8 production, e.g., IL-6 secretion and PEEC (Hepoxilin A3)-induced neutrophil transepithelial migration in response to invasive Salmonella typhimurium. Human IEC have therefore developed LPS-induced signaling cascades that promote an IL-8 hyporesponsiveness to proinflammatory cytokines while LPS exposure does not compromise the ability of IEC to mount other proinflammatory immune responses to invasive enteropathogens.
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