HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: 296/5/L849    most recent 90516.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Cornell, T. T. Articles by Shanley, T. P. Search for Related Content PubMed PubMed Citation Articles by Cornell, T. T. Articles by Shanley, T. P.

Ceramide-dependent PP2A regulation of TNF-induced IL-8 production in respiratory epithelial cells

Divisions of ¹Pediatric Critical Care Medicine and ²Pediatric Pulmonology, Department of Pediatrics and Communicable Diseases, University of Michigan Medical School and C. S. Mott Children's Hospital, Ann Arbor, Michigan

Submitted 8 October 2008 ; accepted in final form 10 March 2009

IL-8 is a key mediator in the pathophysiology of acute lung injury. TNF stimulates IL-8 production in respiratory epithelial cells by activating both the NF-B and MAP kinase pathways. The precise mechanism by which these pathways are downregulated to terminate IL-8 production remains unclear. We studied the regulatory role of the serine/threonine phosphatase, PP2A, on the signaling pathways involved in IL-8 production from respiratory epithelial cells. Inhibition of PP2A using okadaic acid or gene knockdown using siRNA resulted in an augmentation of TNF-induced IL-8 production. We also found that PP2A inhibition resulted in prolonged activation of JNK, p38, and ERK resulting in both increased transcriptional activation of the IL-8 promoter and posttranscriptional stabilization of IL-8 mRNA. Because TNF had been shown to activate ceramide accumulation, and separate studies had linked ceramide with activation of PP2A, we hypothesized the pathway of TNF-inducing ceramide to activate PP2A comprised an endogenous regulatory pathway. Inhibition of the immediate sphingomyelinase-dependent pathway as well as the de novo synthesis pathway of ceramide production reduced serine/threonine phosphatase activity and augmented IL-8 production. These data suggest that ceramide plays a role in activating PP2A to terminate ongoing IL-8 production. In summary, our data suggest that in respiratory epithelium, TNF induces ceramide accumulation, resulting in subsequent activation of PP2A, which targets those kinases responsible for transcriptional activation of IL-8.

interleukin-8; airway epithelium; tumor necrosis factor-; ceramide; phosphatases