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The Heat Shock Response Inhibits RANTES Gene Expression in Cultured Human Lung Epithelium¹

Onsy Ayad^*, James M. Stark, Michael M. Fiedler, Ingrid Y. Menendez^*, Marnie A. Ryan^* and Hector R. Wong^2,*

^* Division of Critical Care Medicine and Division of Pulmonary Medicine, Children’s Hospital Medical Center, Cincinnati, OH 45229

The chemokine RANTES is thought to be involved in the pathophysiology of inflammation-associated acute lung injury. Although much is known regarding signals that induce RANTES gene expression, relatively few data exist regarding signals that inhibit RANTES gene expression. The heat shock response, a highly conserved cellular defense mechanism, has been demonstrated to inhibit a variety of lung proinflammatory responses. We tested the hypothesis that induction of the heat shock response inhibits RANTES gene expression. Treatment of A549 cells with TNF- induced RANTES gene expression in a concentration-dependent manner. Induction of the heat shock response inhibited subsequent TNF--mediated RANTES mRNA expression and secretion of immunoreactive RANTES. Transient transfection assays involving a RANTES promoter-luciferase reporter plasmid demonstrated that the heat shock response inhibited TNF--mediated activation of the RANTES promoter. Inhibition of NF-B nuclear translocation with isohelenin inhibited TNF--mediated RANTES mRNA expression, indicating that RANTES gene expression is NF-B dependent in A549 cells. Induction of the heat shock response inhibited degradation of the NF-B inhibitory protein, I-B but did not significantly inhibit phosphorylation of I-B. We conclude that the heat shock response inhibits RANTES gene expression by a mechanism involving inhibition of NF-B nuclear translocation and subsequent inhibition of RANTES promoter activation. The mechanism by which the heat shock response inhibits NF-B nuclear translocation involves stabilization of I-B, without significantly affecting phosphorylation of I-B.

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