| First Author | Lu Z | Year | 2018 |
| Journal | FASEB J | Volume | 32 |
| Issue | 7 | Pages | 3614-3622 |
| PubMed ID | 29405096 | Mgi Jnum | J:274305 |
| Mgi Id | MGI:6294681 | Doi | 10.1096/fj.201701164R |
| Citation | Lu Z, et al. (2018) A role for heat shock factor 1 in hypercapnia-induced inhibition of inflammatory cytokine expression. FASEB J 32(7):3614-3622 |
| abstractText | 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-kappaB-regulated, innate immune cytokines, TNF-alpha, 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-kappaB activity. In this study, we tested the hypothesis that HSF1 activation in response to hypercapnia results in attenuated NF-kappaB-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-alpha 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-alpha in bronchoalveolar lavage fluid and IL-1beta 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-kappaB 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. |
