TLR2 Promotes Th2/Th17 Responses via TLR4 and TLR7/8 by Abrogating the Type I IFN Amplification Loop

Wenink, Mark H.; Santegoets, Kim C. M.; Broen, Jca; Bon, Lenny van; Abdollahi‐Roodsaz, Shahla; Popa, Călin; Huijbens, R.J.F.; Remijn, Thijs; Lubberts, Erik; Riel, P.L.C.M. van; Berg, Wim B. van den; Radstake, Timothy R. D. J.

doi:10.4049/jimmunol.0900713

Cited by 57 publications

(43 citation statements)

References 52 publications

(53 reference statements)

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“…TLR agonists might be useful not only to boost immunity against microbes and tumors but also to progress autoimmune diseases. Indeed, recent studies have reported that multiple TLR agonists could serve as adjuvants to induce EAE in C57BL/6 mice [26,27]. In our study, APG treatment significantly ameliorated the progression of EAE and down-regulated production of the inflammatory cytokines, IFN-␥, IL-1␤ and IL-17.…”

Section: Discussionmentioning

confidence: 46%

An acidic polysaccharide of Panax ginseng ameliorates experimental autoimmune encephalomyelitis and induces regulatory T cells

Hwang¹,

Ahn²,

Park³

et al. 2011

Immunology Letters

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Section: Discussionmentioning

confidence: 46%

An acidic polysaccharide of Panax ginseng ameliorates experimental autoimmune encephalomyelitis and induces regulatory T cells

Hwang¹,

Ahn²,

Park³

et al. 2011

Immunology Letters

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“…Others have shown that especially TLR2 triggering of DCs can lead to a Th2-cell priming with or without coinduction of Th17 cells [66,67] although there are also other results for Schistosoma antigens that induce Th2-cell responses without the involvement of TLR2, TLR4, or MyD88 [68]. This indicates that quantitatively low TLR signaling but also TLR-and MyD88-independent DC maturation can lead to Th2-cell polarization.…”

Section: Discussionmentioning

confidence: 99%

Similar inflammatory DC maturation signatures induced by TNF or Trypanosoma brucei antigens instruct default Th2‐cell responses

Pletinckx

Stijlemans²,

Pavlović

et al. 2011

Eur J Immunol

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DCs represent the major cell type leading to polarized T-helper (Th) cell responses in vivo. Here, we asked whether the instruction of murine Th2 responses by DCs matured with the proinflammatory cytokine TNF is qualitatively different from maturation by different types of TLR4/MyD88-dependent variant-specific surface glycoproteins (VSGs) of Trypanosoma brucei (T. brucei). The results obtained by analyzing DC surface markers, Notch ligand mRNA, cytokines, asthma, and experimental autoimmune encephalomyelitis (EAE) models as well as performing microarrays indicate that both types of stimuli induce similar inflammatory, semi-mature DC profiles. DCs matured by TNF or VSG treatment expressed a common inflammatory signature of 24 genes correlating with their Th2-polarization capacity. However, the same 24 genes and 4498 additional genes were expressed by DCs treated with LPS that went on to induce Th1 cells. These findings support the concept of a default pathway for Th2-cell induction in DCs matured under suboptimal or inflammatory conditions, independent of the surface receptors and signaling pathways involved. Our data also indicate that quantitative differences in DC maturation might direct Th2-vs Th1-cell responses, since suboptimally matured inflammatory DCs induce default Th2-cell maturation, whereas fully mature DCs induce Th1-cell maturation.Key words: DCs . microarray . Th2 cells . TNF . Trypanosoma Supporting Information available online IntroductionDCs play a fundamental role in the induction of adaptive immune responses as well as in the maintenance of peripheral tolerance [1][2][3]. Through the expression of pattern-recognition receptors (PPRs) such as Toll-like receptors (TLRs), DCs are able to sense a wide array of pathogens and mount an appropriate T-helper (Th) cell response [4]. Naïve CD4 1 T-cell precursors can differentiate into a variety of Th-cell lineages characterized by the cytokines produced: Th1 cells secrete predominately IFN-g, Th2 cells release IL-4, IL-5, and IL-13 and Th17 cells typically produce . Although the contribution of DCs for CD4 1 Th-cell polarization is under debate [6], several DC-derived mechanisms have been described to significantly direct Th-cell phenotypes. 3479DCs change their maturation status by upregulating surface expression of MHC class II and costimulatory molecules and by producing a defined set of cytokines to optimally induce distinct Th-cell responses [7][8][9]. Due to their immunostimulatory function, DCs are of particular interest in immunotherapy settings, such as cancer therapy and infectious disease intervention [10,11]. Thus, the Th-cell polarizing profile defined by the maturation signature of DCs is of vital interest. Several membrane markers on DCs and soluble factors secreted by DCs have been described to polarize toward Th2 responses. These include costimulatory molecules such as OX40 [12], , the Notch family member Jagged-2 [14], the cytokine IL-6 [15], or arachidonic acid metabolites such as PGE 2 [16][17][18]. Much less is known about the fac...

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“…To determine the molecular mechanisms underlying the HCV core/gC1qR-mediated IL-12 suppression, in this study we sought to determine PD-1 and SOCS-1 expression and their role in regulating IL-12 production in human blood-derived M/M F s stimulated with TLR4 ligand-LPS and TLR7/8 ligand-R848, which are known to synergistically induce IL-12 production (35,36). We found that PD-1 and SOCS-1, two negative immunomodulators upregulated by HCV core protein through its interaction with gC1qR on M/M F s, are linked, such that their cross-talk may coordinately deliver negative signaling to TLR-mediated IL-12 production through the Jak/STAT pathway.…”

mentioning

confidence: 99%

Cross-Talk between Programmed Death-1 and Suppressor of Cytokine Signaling-1 in Inhibition of IL-12 Production by Monocytes/Macrophages in Hepatitis C Virus Infection

Zhang

Cheng

et al. 2011

The Journal of Immunology

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Hepatitis C virus (HCV) dysregulates innate immune responses and induces persistent viral infection. We previously demonstrated that HCV core protein impairs IL-12 expression by monocytes/macrophages (M/MΦs) through interaction with a complement receptor gC1qR. Because HCV core-mediated lymphocyte dysregulation occurs through the negative immunomodulators programmed death-1 (PD-1) and suppressor of cytokine signaling-1 (SOCS-1), the aim of this study was to examine their role in HCV core-mediated IL-12 suppression in M/MΦs. We analyzed TLR-stimulated, primary CD14+ M/MΦs from chronically HCV-infected and healthy subjects or the THP-1 cell line for PD-1, SOCS-1, and IL-12 expression following HCV core treatment. M/MΦs from HCV-infected subjects at baseline exhibited comparatively increased PD-1 expression that significantly correlated with the degree of IL-12 inhibition. M/MΦs isolated from healthy and HCV-infected individuals and treated with HCV core protein displayed increased PD-1 and SOCS-1 expression and decreased IL-12 expression, an effect that was also observed in cells treated with gC1qR’s ligand, C1q. Blocking gC1qR rescued HCV core-induced PD-1 upregulation and IL-12 suppression, whereas blocking PD-1 signaling enhanced IL-12 production and decreased the expression of SOCS-1 induced by HCV core. Conversely, silencing SOCS-1 expression using small interfering RNAs increased IL-12 expression and inhibited PD-1 upregulation. PD-1 and SOCS-1 were found to associate by coimmunoprecipitation studies, and blocking PD-1 or silencing SOCS-1 in M/MΦ led to activation of STAT-1 during TLR-stimulated IL-12 production. These data suggested that HCV core/gC1qR engagement on M/MΦs triggers the expression of PD-1 and SOCS-1, which can associate to deliver negative signaling to TLR-mediated pathways controlling expression of IL-12, a key cytokine linking innate and adaptive immunity.

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TLR2 Promotes Th2/Th17 Responses via TLR4 and TLR7/8 by Abrogating the Type I IFN Amplification Loop

Cited by 57 publications

References 52 publications

An acidic polysaccharide of Panax ginseng ameliorates experimental autoimmune encephalomyelitis and induces regulatory T cells

An acidic polysaccharide of Panax ginseng ameliorates experimental autoimmune encephalomyelitis and induces regulatory T cells

Similar inflammatory DC maturation signatures induced by TNF or Trypanosoma brucei antigens instruct default Th2‐cell responses

Cross-Talk between Programmed Death-1 and Suppressor of Cytokine Signaling-1 in Inhibition of IL-12 Production by Monocytes/Macrophages in Hepatitis C Virus Infection

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