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J Biol Chem, Vol. 274, Issue 27, 19447-19454, July 2, 1999

Critical Role of cAMP Response Element Binding Protein Expression in Hypoxia-elicited Induction of Epithelial Tumor Necrosis Factor-

Cormac T. Taylor, Nana Fueki, Azin Agah, Robert M. Hershberg, and Sean P. Colgan

From the Center for Experimental Therapeutics and Reperfusion Injury, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115 and  Virginia Mason Research Center, Seattle, Washington 98101

Tissue hypoxia is intimately associated with a number of chronic inflammatory conditions of the intestine. In this study, we investigated the impact of hypoxia on the expression of a panel of inflammatory mediators by intestinal epithelia. Initial experiments revealed that epithelial (T84 cell) exposure to ambient hypoxia evoked a time-dependent induction of the proinflammatory markers tumor necrosis factor- (TNF-), interleukin-8 (IL-8), and major histocompatibility complex (MHC) class II (37 ± 6.1-, 7 ± 0.8-, and 9 ± 0.9-fold increase over normoxia, respectively, each p < 0.01). Since the gene regulatory elements for each of these molecules contains an NF-B binding domain, we investigated the influence of hypoxia on NF-B activation. Cellular hypoxia induced a time-dependent increase in nuclear p65, suggesting a dominant role for NF-B in hypoxia-elicited induction of proinflammatory gene products. Further work, however, revealed that hypoxia does not influence epithelial intercellular adhesion molecule 1 (ICAM-1) or MHC class I, the promoters of which also contain NF-B binding domains, suggesting differential responses to hypoxia. Importantly, the genes for TNF-, IL-8, and MHC class II, but not ICAM-1 or MHC class I, contain cyclic AMP response element (CRE) consensus motifs. Thus, we examined the role of cAMP in the hypoxia-elicited phenotype. Hypoxia diminished CRE binding protein (CREB) expression. In parallel, T84 cell cAMP was diminished by hypoxia (83 ± 13.2% decrease, p < 0.001), and pharmacologic inhibition of protein kinase A induced TNF- and protein release (9 ± 3.9-fold increase). Addback of cAMP resulted in reversal of hypoxia-elicited TNF- release (86 ± 3.2% inhibition with 3 mM 8-bromo-cAMP). Furthermore, overexpression of CREB but not mutated CREB by retroviral-mediated gene transfer reversed hypoxia-elicited induction of TNF- defining a causal relationship between hypoxia-elicited CREB reduction and TNF- induction. Such data indicate a prominent role for CREB in the hypoxia-elicited epithelial phenotype and implicate intracellular cAMP as an important second messenger in differential induction of proinflammatory mediators.

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