TY - JOUR
T1 - A role for heat shock factor 1 in hypercapnia-induced inhibition of inflammatory cytokine expression
AU - Lu, Ziyan
AU - Casalino-Matsuda, S. Marina
AU - Nair, Aisha
AU - Buchbinder, Anja
AU - Scott Budinger, G. R.
AU - Sporn, Peter H.S.
AU - Gates, Khalilah L.
N1 - Funding Information:
The authors thank Dr. Karen Ridge and Dr. Navdeep Chandel (both from Northwestern University) for advice, reagents, and technical assistance. The authors acknowledge support from the U.S. National Institutes of Health (NIH) National Heart, Lung, and Blood Institute (Grants K01 HL108860, R01 HL131745, and P01 HL071643), and NIH National Institute on Aging (Grant P01 AG049665). The authors declare no conflicts of interest.
PY - 2018/7
Y1 - 2018/7
N2 - 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.
AB - 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.
KW - Bacterial infections
KW - Lung
KW - Macrophage
KW - Rodent
KW - Stress response
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U2 - 10.1096/fj.201701164R
DO - 10.1096/fj.201701164R
M3 - Article
C2 - 29405096
AN - SCOPUS:85049306043
VL - 32
SP - 3614
EP - 3622
JO - FASEB Journal
JF - FASEB Journal
SN - 0892-6638
IS - 7
ER -