Differential regulation of lipopolysaccharide and Gram-positive bacteria induced cytokine and chemokine production in macrophages by G alpha(i) proteins

作者：Fan Hongkuan; Williams David L; Zingarelli Basilia; Breuel Kevin F; Teti Giuseppe; Tempel George E; Spicher Karsten; Boulay Guylain; Birnbaumer Lutz; Halushka Perry V; Cook James A^*

来源：Immunology, 2007, 122(1): 116-123.

DOI：10.1111/j.1365-2567.2007.02619.x

• endotoxin
• G(i) protein-deficient mice
• group B streptococci
• Staphylococcus aureus
• toll-like receptor signalling

Heterotrimeric G(i) proteins play a role in signalling activated by lipopolysaccharide (LPS), Staphylococcus aureus (SA) and group B streptococci (GBS), leading to production of inflammatory mediators. We hypothesized that genetic deletion of G(i) proteins would alter cytokine and chemokine production induced by LPS, SA and GBS stimulation. LPS-induced, heat-killed SA-induced and heat-killed GBS-induced cytokine and chemokine production in peritoneal macrophages from wild-type (WT), G alpha(-/-)(i2) or G alpha(-/-)(i1/3) mice were investigated. LPS induced production of tumour necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), IL-10 and interferon-gamma-inducible protein-10 (IP-10); SA induced TNF-alpha, and IL-1 beta production; and GBS induced TNF-alpha, IL-6, IL-1 beta, macrophage inflammatory protein-1 alpha (MIP-1 alpha) and keratinocyte chemoattract (KC) production were all decreased (P < 0.05) in G alpha(-/-)(i2) or G alpha(-/-)(i1/3) mice compared with WT mice. In contrast to the role of G(i) proteins as a positive regulator of mediators, LPS-induced production of MIP-1 alpha and granulocyte-macrophage colony-stimulating factor (GM-CSF) were increased in macrophages from G alpha(-/-)(i1/3) mice, and SA-induced MIP-1 alpha production was increased in both groups of G alpha(i) protein-depleted mice. LPS-induced production of KC and IL-1 beta, SA-induced production of GM-CSF, KC and IP-10, and GBS-induced production of IL-10, GM-CSF and IP-10 were unchanged in macrophages from G alpha(-/-)(i2) or G alpha(-/-)(i1/3) mice compared with WT mice. These data suggest that G(i2) and G(i1/3) proteins are both involved and differentially regulate murine inflammatory cytokine and chemokine production in response to both LPS and Gram-positive microbial stimuli.

• 出版日期2007-9