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Published ahead of print on March 26, 2008
Am. J. Respir. Cell Mol. Biol. 2008, doi:10.1165/rcmb.2007-0294OC
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Submitted on July 31, 2007
Revised on March 21, 2008

Heat Shock Co-activates Interleukin-8 Transcription

Ishwar S Singh1, Aditi Gupta2, Ashish Nagarsekar2, Zachary Cooper2, Cheu Manka2, Lisa Hester3, Ivor J Benjamin4, Ju-ren He2, and Jeffrey D Hasday5*

1 The Division of Pulmonary and Critical Care Medicine, University of Maryland School of Medicine, Baltimore, MD, USA; Department of Medicine, University of Maryland School of Medicine, The Mucosal Biology Research Center, Baltimore, MD, USA; The Medicine and Research Services of the Baltimore VA Medical Center, Baltimore, MD, USA, 2 The Division of Pulmonary and Critical Care Medicine, University of Maryland School of Medicine, Baltimore, MD, USA, 3 The Division of Pulmonary and Critical Care Medicine, University of Maryland School of Medicine, Baltimore, MD, USA; University of Maryland School of Medicine, The Cytokine Core Laboratory, Baltimore, MD, USA, 4 Department of Medicine, University of Utah School of Medicine, Salt Lake City, UT, USA, 5 The Division of Pulmonary and Critical Care Medicine, University of Maryland School of Medicine, Baltimore, MD, USA; Department of Medicine, University of Maryland School of Medicine, The Mucosal Biology Research Center, Baltimore, MD, USA; University of Maryland School of Medicine, The Cytokine Core Laboratory, Baltimore, MD, USA

* To whom correspondence should be addressed. E-mail: jhasday{at}umaryland.edu.

The heat shock (HS) response is a phylogenetically ancient cellular response to stress, including heat, that shifts gene expression to a set of conserved HS protein (HSP) genes. In our earlier studies, febrile-range hyperthermia (FRH) not only activated HSP gene expression, but also increased expression of CXC chemokines in mice, leading us to hypothesize that the CXC chemokine family of genes might be HS-responsive. To address this hypothesis we analyzed the effect of HS on the expression of interleukin (IL)-8/CXCL-8, a member of the human CXC family of ELR+ chemokines. HS markedly enhanced tumor necrosis factor-{alpha} (TNF{alpha})-induced IL-8 secretion in human A549 respiratory epithelial-like cells and in primary human small airway epithelial cells. IL-8 mRNA was also upregulated by HS, but the stability of IL-8 mRNA was not affected. TNF{alpha}-induced reporter activity of an IL-8 promoter construct IL8-1471/+44-luc stably transfected in A549 cells was also enhanced by HS. Electrophoretic mobility and chromatin immunoprecipitation assays showed that the stress-activated transcription factor heat shock factor-1 (HSF-1) binds to at least two putative heat shock response elements (HRE) present in the IL-8 promoter. Deletional reporter constructs lacking either one or both of these sites showed reduced HS responsiveness. Furthermore, depletion of HSF-1 using siRNA also reduced the effects HS on TNF{alpha}-induced IL-8 expression demonstrating that HSF-1 could also act to regulate IL-8 gene transcription. We speculate that during evolution the CXC chemokine genes may have co-opted elements of the HS response to amplify their expression and enhance neutrophil delivery during febrile illnesses.






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Proc. Am. Thorac. Soc. Am. J. Respir. Crit. Care Med.
Copyright © 2008 American Thoracic Society.