A role for heat shock factor 1 in hypercapnia-induced inhibition of inflammatory cytokine expression

Ziyan Lu, S. Marina Casalino-Matsuda, Aisha Nair, Anja Buchbinder, G. R. Scott Budinger, Peter H.S. Sporn, Khalilah L. Gates*

*Corresponding author for this work

Research output: Contribution to journalArticle

5 Scopus citations

Abstract

Hypercapnia, elevated levels of CO2 in the blood, is a known marker for poor clinical prognosis and is associated with increased mortality in patients hospitalized with both bacterial and viral pneumonias. Although studies have established a connection between elevated CO2 levels and poor pneumonia outcomes, a mechanistic basis of this association has not yet been established. We previously reported that hypercapnia inhibits expression of key NF-kB–regulated, innate immune cytokines, TNF-a, and IL-6, in LPS-stimulated macrophages in vitro and in mice during Pseudomonas pneumonia. The transcription factor heat shock factor 1 (HSF1) is important in maintaining proteostasis during stress and has been shown to negatively regulate NF-kB activity. In this study, we tested the hypothesis that HSF1 activation in response to hypercapnia results in attenuated NF-kB–regulated gene expression. We found that hypercapnia induced the protein expression and nuclear accumulation of HSF1 in primary murine alveolar macrophages and in an alveolar macrophage cell line (MH-S). In MH-S cells treated with short interfering RNA targeting Hsf1, LPS-induced IL-6 and TNF-a release were elevated during exposure to hypercapnia. Pseudomonas-infected Hsf1+/+ (wild-type) mice, maintained in a hypercapnic environment, showed lower levels of IL-6 and TNF-a in bronchoalveolar lavage fluid and IL-1b in lung tissue than did infected mice maintained in room air. In contrast, infected Hsf1+/2 mice exposed to either hypercapnia or room air had similarly elevated levels of those cytokines. These results suggest that hypercapnia-mediated inhibition of NF-kB cytokine production is dependent on HSF1 expression and/or activation.—Lu, Z., Casalino-Matsuda, S. M., Nair, A., Buchbinder, A., Budinger, G. R. S., Sporn, P. H. S., Gates, K. L. A role for heat shock factor 1 in hypercapnia-induced inhibition of inflammatory cytokine expression.

Original languageEnglish (US)
Pages (from-to)3614-3622
Number of pages9
JournalFASEB Journal
Volume32
Issue number7
DOIs
StatePublished - Jul 2018

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Keywords

  • Bacterial infections
  • Lung
  • Macrophage
  • Rodent
  • Stress response

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

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