Faculty Collaboration Database

Heat shock co-activates interleukin-8 transcription. Am J Respir Cell Mol Biol 2008 Aug;39(2):235-42

Date

03/28/2008

Pubmed ID

18367728

Pubmed Central ID

PMC2542457

DOI

10.1165/rcmb.2007-0294OC

Scopus ID

2-s2.0-48649092274 (requires institutional sign-in at Scopus site)   51 Citations

Abstract

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 IL-8/CXCL-8, a member of the human CXC family of ELR(+) chemokines. HS markedly enhanced 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 up-regulated 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 (HSE) 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.

Author List

Singh IS, Gupta A, Nagarsekar A, Cooper Z, Manka C, Hester L, Benjamin IJ, He JR, Hasday JD

Author

Ivor J. Benjamin MD Center Director, Professor in the Medicine department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Cell Line
DNA-Binding Proteins
Fever
Heat Shock Transcription Factors
Heat-Shock Proteins
Heat-Shock Response
Humans
Interleukin-8
Mice
Mice, Knockout
Transcription Factors
Transcriptional Activation
Tumor Necrosis Factor-alpha