title: Elevated CO2 selectively inhibits interleukin-6 and tumor necrosis factor expression and decreases phagocytosis in the macrophage.
abstract: Elevated blood and tissue CO(2), 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 P(CO2) 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)-kappaB-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-beta, which do not require NF-kappaB. Notably, hypercapnia did not affect LPS-induced degradation of IkappaB alpha, 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 P(CO2) 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.
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University, 240 E. Huron St., Chicago, IL 60611, USA.
authors.forename: Naizhen
authors.initials: N
authors.lastname: Wang
authors.forename: Khalilah L
authors.initials: KL
authors.lastname: Gates
authors.forename: Humberto
authors.initials: H
authors.lastname: Trejo
authors.forename: Silvio
authors.initials: S
authors.lastname: Favoreto
authors.forename: Robert P
authors.initials: RP
authors.lastname: Schleimer
authors.forename: Jacob I
authors.initials: JI
authors.lastname: Sznajder
authors.forename: Greg J
authors.initials: GJ
authors.lastname: Beitel
authors.forename: Peter H S
authors.initials: PH
authors.lastname: Sporn
mesh_terms: D000818:Animals; D002245:Carbon Dioxide / Q000494:pharmacology*; D045744:Cell Line, Tumor; D016207:Cytokines / Q000096:biosynthesis; D006801:Humans; D006935:Hypercapnia / Q000276:immunology*; D007113:Immunity, Innate / Q000187:drug effects; D015850:Interleukin-6 / Q000096:biosynthesis; D016676:Macrophages, Alveolar / Q000187:drug effects / Q000276:immunology*; D051379:Mice; D010587:Phagocytosis / Q000187:drug effects*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D000093242:Interleukin-6 Inhibitors
chemical_list: D002245:Carbon Dioxide; D016207:Cytokines; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D000093242:Interleukin-6 Inhibitors