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 language | English (US) |
|---|---|
| Pages (from-to) | 3614-3622 |
| Number of pages | 9 |
| Journal | FASEB Journal |
| Volume | 32 |
| Issue number | 7 |
| DOIs | |
| State | Published - Jul 1 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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A role for heat shock factor 1 in hypercapnia-induced inhibition of inflammatory cytokine expression. / Lu, Ziyan; Casalino Matsuda, Marina Susana; Nair, Aisha; Buchbinder, Anja; Budinger, GR Scott; Sporn, Peter H; Gates, Khalilah Latrece.
In: FASEB Journal, Vol. 32, No. 7, 01.07.2018, p. 3614-3622.Research output: Contribution to journal › Article
TY - JOUR
T1 - A role for heat shock factor 1 in hypercapnia-induced inhibition of inflammatory cytokine expression
AU - Lu, Ziyan
AU - Casalino Matsuda, Marina Susana
AU - Nair, Aisha
AU - Buchbinder, Anja
AU - Budinger, GR Scott
AU - Sporn, Peter H
AU - Gates, Khalilah Latrece
PY - 2018/7/1
Y1 - 2018/7/1
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
UR - http://www.scopus.com/inward/record.url?scp=85049306043&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85049306043&partnerID=8YFLogxK
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 -