Differential regulation of lipopolysaccharide and Gram‐positive bacteria induced cytokine and chemokine production in macrophages by Gα_i proteins

Abstract

Summary Heterotrimeric Gi 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 Gi 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), Gαi2–/– or Gαi1/3–/– mice were investigated. LPS induced production of tumour necrosis factor‐α (TNF‐α), interleukin‐6 (IL‐6), IL‐10 and interferon‐γ‐inducible protein‐10 (IP‐10); SA induced TNF‐α, and IL‐1β production; and GBS induced TNF‐α, IL‐6, IL‐1β, macrophage inflammatory protein‐1α (MIP‐1α) and keratinocyte chemoattract (KC) production were all decreased (P < 0·05) in Gαi2–/– or Gαi1/3–/– mice compared with WT mice. In contrast to the role of Gi proteins as a positive regulator of mediators, LPS‐induced production of MIP‐1α and granulocyte–macrophage colony‐stimulating factor (GM‐CSF) were increased in macrophages from Gαi1/3–/– mice, and SA‐induced MIP‐1α production was increased in both groups of Gαi protein‐depleted mice. LPS‐induced production of KC and IL‐1β, 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 Gαi2–/– or Gαi1/3–/– mice compared with WT mice. These data suggest that Gi2 and Gi1/3 proteins are both involved and differentially regulate murine inflammatory cytokine and chemokine production in response to both LPS and Gram‐positive microbial stimuli.

Defective Macrophage Migration in Gαi2- but Not Gαi3-Deficient Mice

“…3). The latter observation is in agreement with the findings of Fan et al (39), who suggested that Ga i2 and Ga i3 are both involved in LPSinduced cell activation. However, we also note that Ga i3 -deficient mice exhibit an increased accumulation of macrophages in lung tissue in response to LPS ( Fig.…”

Group B Streptococcus and Streptococcus suis Capsular Polysaccharides Induce Chemokine Production by Dendritic Cells via Toll-Like Receptor 2- and MyD88-Dependent and -Independent Pathways

“…Recently, whole S. suis type 2 was shown to induce CCL2 production by murine DCs (12) and CCL3 production by total mouse splenocytes (unpublished data). Similarly, studies have shown that whole GBS type III stimulates CCL2 and CCL3 secretion by murine macrophages and/or DCs (85,86). Our observations with purified CPSs allow a better interpretation of previous data showing different patterns of chemokine production obtained with total leukocytes, monocytes, and/or DCs cultured in the presence of whole S. suis type 2 or GBS types III and V and their respective nonencapsulated mutants.…”

An obligatory requirement for the heterotrimeric G protein G i3 in the antiautophagic action of insulin in the liver

“…The initial analysis of G␣ i3 -deficient mice did not reveal overt phenotypic defects (5,6). However, the comparative analysis of G␣ i1 /G␣ i3 -double-deficient with G␣ i2 -deficient mice led to the identification of overlapping as well as gene-specific functions of G i isoforms in the antiinfectious response of macrophages and splenocytes (7). Recent studies of G␣ i3 mutant mice have revealed craniofacial and other skeletal deformities consistent with a specific requirement for G␣ i3 in the cranial neural crest and in somites (N. W. Plummer, K.S., J. Malphurs, L.B., unpublished work).…”