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A role for heat shock factor 1 in hypercapnia‐induced inhibition of inflammatory cytokine expression
Author(s) -
Lu Ziyan,
CasalinoMatsuda S. Marina,
Nair Aisha,
Buchbinder Anja,
Budinger G. R. Scott,
Sporn Peter H. S.,
Gates Khalilah L.
Publication year - 2018
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.201701164r
Subject(s) - hypercapnia , bronchoalveolar lavage , cytokine , tumor necrosis factor alpha , inflammation , immunology , hsf1 , proinflammatory cytokine , heat shock , heat shock protein , biology , medicine , lung , hsp70 , respiratory system , biochemistry , gene
Hypercapnia, elevated levels of CO 2 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 CO 2 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‐κB‐regulated, innate immune cytokines, TNF‐α, 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‐κB activity. In this study, we tested the hypothesis that HSF1 activation in response to hypercapnia results in attenuated NF‐κB‐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‐α 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‐α in bronchoalveolar lavage fluid and IL‐1β in lung tissue than did infected mice maintained in room air. In contrast, infected Hsf1 +/• mice exposed to either hypercapnia or room air had similarly elevated levels of those cytokines. These results suggest that hypercapnia‐mediated inhibition of NF‐κB 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. FASEB J. 32, 3614–3622 (2018). www.fasebj.org