Elevated CO2 selectively inhibits interleukin-6 and tumor necrosis factor expression and decreases phagocytosis in the macrophage

Naizhen Wang, Khalilah L. Gates, Humberto Trejo, Silvio Favoreto, Robert P. Schleimer, Jacob I. Sznajder, Greg J. Beitel, Peter H S Sporn

Research output: Contribution to journalArticlepeer-review

75 Scopus citations

Abstract

Elevated blood and tissue CO2, or hypercapnia, is common in severe lung disease. Patients with hypercapnia often develop lung infections and have an increased risk of death following pneumonia. To explore whether hypercapnia interferes with host defense, we studied the effects of elevated PCO2 on macrophage innate immune responses. In differentiated human THP-1 macrophages and human and mouse alveolar macrophages stimulated with lipopolysaccharide (LPS) and other Toll-like receptor ligands, hypercapnia inhibited expression of tumor necrosis factor and interleukin (IL)-6, nuclear factor (NF)-κB-dependent cytokines critical for antimicrobial host defense. Inhibition of IL-6 expression by hypercapnia was concentration dependent, rapid, reversible, and independent of extracellular and intracellular acidosis. In contrast, hypercapnia did not down-regulate IL-10 or interferon-β, which do not require NF-κB. Notably, hypercapnia did not affect LPS-induced degradation of IκBα, nuclear translocation of RelA/p65, or activation of mitogen-activated protein kinases, but it did block IL-6 promoter-driven luciferase activity in mouse RAW 264.7 macrophages. Elevated PCO2 also decreased phagocytosis of opsonized polystyrene beads and heat-killed bacteria in THP-1 and human alveolar macrophages. By interfering with essential innate immune functions in the macrophage, hypercapnia may cause a previously unrecognized defect in resistance to pulmonary infection in patients with advanced lung disease.

Original languageEnglish (US)
Pages (from-to)2178-2190
Number of pages13
JournalFASEB Journal
Volume24
Issue number7
DOIs
StatePublished - Jul 2010

Keywords

  • Cytokines
  • Lipopolysaccharide
  • Lung
  • Monocytes
  • Phagocytosis

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

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