Role of the Phosphatidylinositol 3 Kinase-Akt Pathway in the Regulation of IL-10 and IL-12 by<i>Porphyromonas gingivalis</i>Lipopolysaccharide

Martin, Michael; Schifferle, Robert E.; Cuesta, Natalia; Vogel, Stefanie N.; Katz, Jannet; Michalek, Suzanne M.

doi:10.4049/jimmunol.171.2.717

Cited by 229 publications

(248 citation statements)

References 83 publications

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“…It had been demonstrated that the inhibition of ERK or PI3K by selective inhibitors (PD98059 or LY294002) significantly enhanced the phenotypic and functional maturation of human MoDCs. These reports support our notion regarding the negative effects of the ERK and PI3K signaling pathways on IL-12 production, and their inhibitory effect on DC maturation (39,40). We also examined the effect of WKYMVm on the expressions of the LPS receptors TLR4 and TLR2 by using FACS.…”

Section: Discussionsupporting

confidence: 67%

The Synthetic Peptide Trp-Lys-Tyr-Met-Val-D-Met Inhibits Human Monocyte-Derived Dendritic Cell Maturation via Formyl Peptide Receptor and Formyl Peptide Receptor-Like 2

Kang¹,

Lee

Kim

et al. 2005

The Journal of Immunology

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Trp-Lys-Tyr-Met-Val-D-Met (WKYMVm) has been reported to stimulate monocytes, neutrophils, and dendritic cells (DCs). However, although WKYMVm has been reported to function as a DC chemoattractant, its role on DC maturation has not been examined. In this study, we investigated the effects of WKYMVm on human DC maturation. The costimulation of DCs with WKYMVm and LPS dramatically inhibited LPS-induced IL-12 production, CD86 and HLA-DR surface expression, and DC-mediated T cell proliferation. However, DC phagocytic activity was increased by WKYMVm stimulation. These findings demonstrate that WKYMVm inhibits DC maturation by LPS. In terms of the mechanism underlying DC maturation inhibition by WKYMVm, we found that LPS-induced DC maturation was negatively regulated by WKYMVm-stimulated ERK activity. Moreover, the costimulation of DCs with WKYMVm and LPS dramatically inhibited the LPS-induced accumulations of IL-12 mRNA, thus suggesting that WKYMVm inhibits LPS-induced IL-12 production at the transcriptional level. We also found that DCs express two WKYMVm receptors, formyl peptide receptor (FPR) and FPR-like 2 (FPRL2). In addition, formyl-Met-Leu-Phe (a FPR ligand), Trp-Lys-Tyr-Met-Val-Met, Hp(2–20) peptide, and F2L (three FPRL2 ligands) inhibited LPS-induced IL-12 production in DCs. Taken together, our findings indicate that the activations of FPR and FPRL2 inhibit LPS-induced DC maturation, and suggest that these two receptors should be regarded as important potential therapeutic targets for the modulation of DC maturation.

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Section: Discussionsupporting

confidence: 67%

The Synthetic Peptide Trp-Lys-Tyr-Met-Val-D-Met Inhibits Human Monocyte-Derived Dendritic Cell Maturation via Formyl Peptide Receptor and Formyl Peptide Receptor-Like 2

Kang¹,

Lee

Kim

et al. 2005

The Journal of Immunology

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“…Thus, diminished CR3 outside-in signaling by the FimCDE mutants would not only result in higher IL-12 induction, but also reduced ERK1/2 activation downstream of CR3. Reduced ERK1/2 activation may in turn result in decreased production of the antiinflammatory IL-10 (Martin et al, 2003).…”

Section: In Vivo Evidence For Cr3 Exploitation By P Gingivalis and Imentioning

confidence: 99%

Subversion of Innate Immunity by Periodontopathic Bacteria via Exploitation of Complement Receptor-3

Hajishengallis

Wang²,

Liang³

et al. 2008

Advances in Experimental Medicine and Biology

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The capacity of certain pathogens to exploit innate immune receptors enables them to undermine immune clearance and persist in their host, often causing disease. Here we review subversive interactions of Porphyromonas gingivalis, a major periodontal pathogen, with the complement receptor-3 (CR3; CD11b/CD18) in monocytes/macrophages. Through its cell surface fimbriae, P. gingivalis stimulates Toll-like receptor-2 (TLR2) inside-out signaling which induces the highaffinity conformation of CR3. Although this activates CR3-dependent monocyte adhesion and transendothelial migration, P. gingivalis has co-opted this TLR2 proadhesive pathway for CR3 binding and intracellular entry. In CR3-deficient macrophages, the internalization of P. gingivalis is reduced 2-fold but its ability to survive intracellularly is reduced 1000-fold, indicating that CR3 is exploited by the pathogen as a relatively safe portal of entry. The interaction of P. gingivalis fimbriae with CR3 additionally inhibits production of bioactive (p70) interleukin-12, which mediates immune clearance. In vivo blockade of CR3 leads to reduced persistence of P. gingivalis in the mouse host and diminished ability to cause periodontal bone loss, the hallmark of periodontal disease. Strikingly, the ability of P. gingivalis to interact with and exploit CR3 depends upon quantitatively minor components (FimCDE) of its fimbrial structure, which predominantly consists of polymerized fimbrillin (FimA). Indeed, isogenic mutants lacking FimCDE but expressing FimA are dramatically less persistent and virulent than the wild-type organism both in vitro and in vivo. This model of immune evasion through CR3 exploitation by P. gingivalis supports the concept that pathogens evolved to manipulate innate immune function for promoting their adaptive fitness.

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“…To further investigate the basis of the differential cross-regulation of the TLRs, we investigated the role of the phosphatidylinositol 3-kinase (PI3K/Akt) pathway implicated in the regulation of TLR signaling and cytokine production (Guha and Mackman, 2002;Martin et al, 2003). In mIC cl2 cells, specific inhibition of PI3K with wortmannin (Hazeki et al, 2006;Yano et al, 1993) caused an increase of NF-B luciferase activity in response to Pam 3 CSK 4 , LPS as well as flagellin (Fig.…”

Section: Contribution Of the Pi3k/akt Pathway To Tlr Cross-regulationmentioning

confidence: 99%

Ligand-induced differential cross-regulation of Toll-like receptors 2, 4 and 5 in intestinal epithelial cells

Aubel

Keestra

Krooshoop

et al. 2007

Molecular Immunology

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Toll-like receptors (TLR) 2, TLR4 and TLR5 are primary mucosal sensors of microbial patterns. Dissection of the cross-talk between TLRs in intestinal cells has thus far been hampered by the lack of functional TLR2 and TLR4 in in vitro model systems. Here we report that the mouse intestinal epithelial cell line mIC cl2 expresses these TLRs and that receptor expression and function are regulated by environmental TLR stimuli. Our results show that stimulation of TLR5 by bacterial flagellin resulted in upregulated TLR2 and TLR4 mRNA and concomitant sensitization of the cells for subsequent TLR2 (Pam 3 CSK 4 ) and TLR4 (LPS) stimulation. Exposure to low amounts of either Pam 3 CSK 4 or LPS in turn downregulated TLR5 mRNA and attenuated subsequent flagellin-mediated NF-B activation, pointing to a negative feedback mechanism. Pam 3 CSK 4 and LPS also downregulated TLR4 mRNA but upregulated TLR2 mRNA and sensitized cells for subsequent TLR2 stimulation. Inhibition of the phosphatidylinositol-3-kinase/Akt pathway only affected LPS-mediated TLR cross-talk indicating that differential TLR cross-regulation was conferred via different mechanisms. Together, our results demonstrate that the expression and function of TLR in intestinal cells are highly dynamic and tightly regulated in response to encountered bacterial stimuli.

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Role of the Phosphatidylinositol 3 Kinase-Akt Pathway in the Regulation of IL-10 and IL-12 byPorphyromonas gingivalisLipopolysaccharide

Cited by 229 publications

References 83 publications

The Synthetic Peptide Trp-Lys-Tyr-Met-Val-D-Met Inhibits Human Monocyte-Derived Dendritic Cell Maturation via Formyl Peptide Receptor and Formyl Peptide Receptor-Like 2

The Synthetic Peptide Trp-Lys-Tyr-Met-Val-D-Met Inhibits Human Monocyte-Derived Dendritic Cell Maturation via Formyl Peptide Receptor and Formyl Peptide Receptor-Like 2

Subversion of Innate Immunity by Periodontopathic Bacteria via Exploitation of Complement Receptor-3

Ligand-induced differential cross-regulation of Toll-like receptors 2, 4 and 5 in intestinal epithelial cells

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