Premium
Elevated CO 2 selectively inhibits interleukin‐6 and tumor necrosis factor expression and decreases phagocytosis in the macrophage
Author(s) -
Wang Naizhen,
Gates Khalilah L.,
Trejo Humberto,
Favoreto Silvio,
Schleimer Robert P.,
Sznajder Jacob I.,
Beitel Greg J.,
Sporn Peter H. S.
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.09-136895
Subject(s) - tumor necrosis factor alpha , phagocytosis , innate immune system , lipopolysaccharide , biology , hypercapnia , macrophage , alveolar macrophage , immunology , chemistry , microbiology and biotechnology , immune system , endocrinology , acidosis , biochemistry , in vitro
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)‐KB‐ 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‐ß, 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 P CO 2 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.—Wang, N., Gates, K. L., Trejo, H., Favoreto, Jr., S., Schleimer, R P., Sznajder, J. I., Beitel, G. J., Sporn, P. H. S. Elevated CO 2 selectively inhibits interleukin‐6 and tumor necrosis factor expression and decreases phagocytosis in the macrophage. FASEB J. 24, 2178–2190 (2010). www.fasebj.org