Lipopolysaccharide- and gram-positive bacteria-induced cellular inflammatory responses: role of heterotrimeric Gα<sub>i</sub> proteins

Fan, Hongkuan; Zingarelli, Basilia; Peck, Octavia M; Teti, Giuseppe; Tempel, G; Halushka, Perry V.; Cook, James A.

doi:10.1152/ajpcell.00394.2004

Cited by 43 publications

(50 citation statements)

References 67 publications

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“…In the present study, the total numbers of cells and specifically, neutrophils recruited into the micro-environment of the larvae were significantly lower in Gαi2 −/− mice as compared with wild-type mice. This confirms previous observations that disruption of signaling through Gαi proteins inhibits cell migration and recruitment to infection sites [35][36][37] and contradicts studies that demonstrated that Gαi2 −/− mice have equal or enhanced MPO levels, used as a measurement of neutrophil recruitment in the gut, liver, or lung following exposure to LPS [38]. It is clear from the present study that Gαi2 is required for neutrophil recruitment to the s.c. microenvironment of the nematode parasite.…”

Section: Discussionsupporting

confidence: 92%

“…This is in contrast to neutrophils recovered from TLR4-deficient mice, which were able to migrate to the parasite but were unable to kill the worms [24]. Although TLR4 and Gαi are linked in their activation and function [23,38], it can be concluded from the present study that Gαi2 protein is not required for TLR4-dependent neutrophil killing of the larvae. Neutrophils from TLR4-deficient mice cannot kill larvae [24], although they migrate to the site, whereas neutrophils from Gαi2-deficient mice can kill the larvae as efficiently as wild-type cells only if they are transported experimentally to the site of infection.…”

Section: Discussioncontrasting

confidence: 88%

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Signaling through Gαi2 protein is required for recruitment of neutrophils for antibody-mediated elimination of larvalStrongyloides stercoralisin mice

Padigel

Stein

Redding

et al. 2007

Journal of Leukocyte Biology

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The heterotrimeric guanine nucleotide-binding protein Gαi2 is involved in regulation of immune responses against microbial and nonmicrobial stimuli. Gαi2 −/− mice have a selectively impaired IgM response consistent with a disorder in B cell development yet have augmented T cell effector function associated with increased production of IFN-γ and IL-4. The goal of the present study was to determine if a deficiency in the Gαi2 protein in mice would affect the protective immune response against Strongyloides stercoralis, which is IL-4-, IL-5-, and IgM-dependent. Gαi2 −/− and wild-type mice were immunized and challenged with S. stercoralis larvae and analyzed for protective immune responses against infection. Gαi2 −/− mice failed to kill the larvae in the challenge infection as compared with wild-type mice, despite developing an antigen-specific Th2 response, characterized by increased IL-4, IL-5, IgM, and IgG. Transfer of serum collected from immunized Gαi2 −/− mice to naïve, wild-type mice conferred passive, protective immunity against S. stercoralis infection, thus confirming the development of a protective antibody response in Gαi2 −/− mice. Differential cell analyses and myeloperoxidase assays for quantification of neutrophils showed a significantly reduced recruitment of neutrophils into the microenvironment of the parasites in immunized Gαi2 −/− mice. However, cell transfer studies demonstrated that neutrophils from Gαi2 −/− mice are competent in killing larvae. These data demonstrate that Gαi2 signaling events are not required for the development of the protective immune responses against S. stercoralis; however, Gαi2 is essential for the recruitment of neutrophils required for host-dependent killing of larvae.

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Section: Discussionsupporting

confidence: 92%

Section: Discussioncontrasting

confidence: 88%

Signaling through Gαi2 protein is required for recruitment of neutrophils for antibody-mediated elimination of larvalStrongyloides stercoralisin mice

Padigel

Stein

Redding

et al. 2007

Journal of Leukocyte Biology

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“…Heterotrimeric guanine nucleotidebinding regulatory (Gi) proteins modulate LPS signaling pathways and downstream pro-inflammatory gene expression (4)(5)(6)(7). In addition to toll-like receptor (TLR) 4, LPS also binds to a cluster of receptors in lipid rafts, some of which are Gi protein coupled (8).…”

Section: Introductionmentioning

confidence: 99%

“…In addition to toll-like receptor (TLR) 4, LPS also binds to a cluster of receptors in lipid rafts, some of which are Gi protein coupled (8). Our previous studies demonstrated that LPS-induced inflammatory cytokines and chemokines were augmented in vitro and in vivo in Gi proteindeficient mice compared with WT mice, suggesting an anti-inflammatory role of Gi proteins (5,6). Gi protein-coupled ERK 1/2 signaling pathway mediates LPSinduced signaling (4).…”

Section: Introductionmentioning

confidence: 99%

Lysophosphatidic Acid Inhibits Bacterial Endotoxin-Induced Pro-Inflammatory Response: Potential Anti-Inflammatory Signaling Pathways

Fan

Zingarelli

Harris

et al. 2008

Mol Med

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Previous studies have demonstrated that heterotrimeric guanine nucleotide-binding regulatory (Gi) protein-deficient mice exhibit augmented inflammatory responses to lipopolysaccharide (LPS). These findings suggest that Gi protein agonists will suppress LPS-induced inflammatory gene expression. Lysophosphatidic acid (LPA) activates G protein-coupled receptors leading to Gi protein activation. We hypothesized that LPA will inhibit LPS-induced inflammatory responses through activation of Gi-coupled anti-inflammatory signaling pathways. We examined the anti-inflammatory effect of LPA on LPS responses both in vivo and in vitro in CD-1 mice. The mice were injected intravenously with LPA (10 mg/kg) followed by intraperitoneal injection of LPS (75 mg/kg for survival and 25 mg/kg for other studies). LPA significantly increased the mice survival to endotoxemia (P < 0.05). LPA injection reduced LPS-induced plasma TNF-α production (69 ± 6%, P < 0.05) and myeloperoxidase (MPO) activity in lung (33 ± 9%, P < 0.05) as compared to vehicle injection. LPS-induced plasma IL-6 was unchanged by LPA. In vitro studies with peritoneal macrophages paralleled results from in vivo studies. LPA (1 and 10 μM) significantly inhibited LPS-induced TNFα production (61 ± 9% and 72 ± 9%, respectively, P < 0.05) but not IL-6. We further demonstrated that the anti-inflammatory effect of LPA was reversed by ERK 1/2 and phosphatase inhibitors, suggesting that ERK 1/2 pathway and serine/threonine phosphatases are involved. Inhibition of phosphatidylinositol 3 (PI3) kinase signaling pathways also partially reversed the LPA anti-inflammatory response. However, LPA did not alter NFκB and peroxisome proliferator-activated receptor γ (PPARγ) activation. Inhibitors of PPARγ did not alter LPA-induced inhibition of LPS signaling. These studies demonstrate that LPA has significant anti-inflammatory activities involving activation of ERK 1/2, serine/threonine phosphatases, and PI3 kinase signaling pathways.

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“…Genetic deletion of the G␣ i isoforms (G␣ i1 , G␣ i2 , and G␣ i3 ) suggests that G ␣i proteins differentially regulate TLR-stimulated cytokine production in a cell-type specific manner (16). However, the role of G␣ i/o proteins in TLR4 signaling in endothelial cells remains less well understood and the role of G␣ i/o in TLR signaling cascades other than TLR4 has not been shown.…”

mentioning

confidence: 99%

Heterotrimeric G_i/G_oproteins modulate endothelial TLR signaling independent of the MyD88-dependent pathway

Dauphinee¹,

Voelcker

Tebaykina

et al. 2011

American Journal of Physiology-Heart and Circulatory Physiology

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The innate immune recognition of bacterial lipopolysaccharide (LPS) is mediated by Toll-like receptor 4 (TLR4) and results in activation of proinflammatory signaling including NF-B and MAPK pathways. Heterotrimeric G proteins have been previously implicated in LPS signaling in macrophages and monocytes. In the present study, we show that pertussis toxin sensitive heterotrimeric G proteins (G␣i/o) are involved in the activation of MAPK and Akt downstream of TLR2, TLR3, and TLR4 in endothelial cells. G␣ i/o are also required for full activation of interferon signaling downstream of TLR3 and TLR4 but are not required for the activation of NF-B. We find that G␣i/o-mediated activation of the MAPK is independent of the canonical MyD88, interleukin-1 receptor-associated kinase, and tumor necrosis factor receptor-associated factor 6 signaling cascade in LPS-stimulated cells. Taken together, the data presented here suggest that heterotrimeric G proteins are widely involved in TLR pathways along a signaling cascade that is distinct from MyD88-TRAF6.lipopolysaccharide; innate immunity; toll-like receptors; heterotrimeric G proteins; myeloid differentiation factor THE INNATE IMMUNE RECOGNITION of bacterial and viral products is mediated by a family of transmembrane receptors known as Toll-like receptors (TLRs). Lipopolysaccharide (LPS), a key component of the outer wall of gram-negative bacteria, initiates endothelial activation through a receptor complex consisting of TLR4, CD14, and MD2 (9). Recruitment of the adaptor proteins TIR-containing adaptor molecule (TIRAP) and myeloid differentiation factor (MyD88) initiates a MyD88-dependent pathway that culminates in the activation of NF-B and MAPK. Activation of these downstream targets requires recruitment of interleukin-1 receptor-associated kinase (IRAK4) and IRAK1 through interaction between the death domains of MyD88 and the IRAKs. The autophosphorylation and activation of IRAK1 results in the ability to bind tumor necrosis factor receptor-associated factor 6 (TRAF6) (7), which leads to oligomerization and polyubiquitination of the TRAF6 molecule (11). This facilitates activation of transforming growth factor-␤ (TGF-␤)-activated kinase 1, which leads to activation of the IKK-NF-B pathway and the three MAPK: p38, ERK, and JNK (39). In addition to the MyD88-dependent pathway, LPS stimulation also results in the activation of a MyD88-independent pathway, through recruitment of the adaptor molecules TIR-containing adaptor inducing IFN-␤ (TRIF) and TRIF-related adaptor molecule. This leads to the late-phase activation of NF-B and interferon regulatory factor 3 (IRF3), as well as activation of the MAPKs and phosphatidylinositol 3-kinase (PI3K) (10).The endothelium plays a major role in the pathogenesis of sepsis. Under normal conditions, the endothelium functions to maintain organ homeostasis through vasoregulation, selective vascular permeability, and providing an anticoagulant surface. During bacterial infection, the normal physiological functions of the endothelium are pert...

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Lipopolysaccharide- and gram-positive bacteria-induced cellular inflammatory responses: role of heterotrimeric Gα_i proteins

Cited by 43 publications

References 67 publications

Signaling through Gαi2 protein is required for recruitment of neutrophils for antibody-mediated elimination of larvalStrongyloides stercoralisin mice

Signaling through Gαi2 protein is required for recruitment of neutrophils for antibody-mediated elimination of larvalStrongyloides stercoralisin mice

Lysophosphatidic Acid Inhibits Bacterial Endotoxin-Induced Pro-Inflammatory Response: Potential Anti-Inflammatory Signaling Pathways

Heterotrimeric G_i/G_oproteins modulate endothelial TLR signaling independent of the MyD88-dependent pathway

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Lipopolysaccharide- and gram-positive bacteria-induced cellular inflammatory responses: role of heterotrimeric Gαi proteins

Cited by 43 publications

References 67 publications

Signaling through Gαi2 protein is required for recruitment of neutrophils for antibody-mediated elimination of larvalStrongyloides stercoralisin mice

Signaling through Gαi2 protein is required for recruitment of neutrophils for antibody-mediated elimination of larvalStrongyloides stercoralisin mice

Lysophosphatidic Acid Inhibits Bacterial Endotoxin-Induced Pro-Inflammatory Response: Potential Anti-Inflammatory Signaling Pathways

Heterotrimeric Gi/Goproteins modulate endothelial TLR signaling independent of the MyD88-dependent pathway

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Product

Resources

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Lipopolysaccharide- and gram-positive bacteria-induced cellular inflammatory responses: role of heterotrimeric Gα_i proteins

Heterotrimeric G_i/G_oproteins modulate endothelial TLR signaling independent of the MyD88-dependent pathway