Toll-Like Receptor Signaling Mechanisms Involved in Dendritic Cell Activation: Potential Therapeutic Control of T Cell Polarization

Amati, L.; Pepe, Maria; Passeri, Maria Elena; Mastronardi, Maria; Jirillo, Emilio; Covelli, Venusia

doi:10.2174/138161206778743583

Cited by 48 publications

(43 citation statements)

References 88 publications

(153 reference statements)

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“…TLRs are expressed in the respiratory epithelial cells and many types of immune cells including mast cells, DCs, T cells, B cells, endothelium, fibroblasts, and vascular smooth muscle (20,21). Following PAMPs or DAMPs binding, TLRs or non-TLRs are able to regulate the function of these cells and skew specific immune responses toward the Th1, Th2, Th17 or Tregs phenotype according to the antigenic stimulation involved (22). In the family of TLRs, TLR2 is a unique member that mediates a TH1 response on one hand (23) and TH2-biased response on the other (24).…”

Section: Discussionmentioning

confidence: 99%

Targeting TLR2 Attenuates Pulmonary Inflammation and Fibrosis by Reversion of Suppressive Immune Microenvironment

Yang

Cui

Liu

et al. 2009

The Journal of Immunology

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Pulmonary fibrosis is a consequence of chronic lung injury and is associated with a high mortality. Despite the pathogenesis of pulmonary fibrosis remaining as an enigma, immune responses play a critical role in the deregulation of wound healing process after lung injury, which leads to fibrosis. Accumulating evidence argues the rationales for current treatments of pulmonary fibrosis using immunosuppressive agents such as corticosteroids. In this study, we report that bleomycin (BLM), a well-known fibrogenic agent functioning as a TLR2 agonist, induced the maturation of dendritic cells and release of cytokines. The BLM activation of TLR2 mediated a time-dependent alteration of immune responses in the lung. These responses resulted in an increase in the tissue-infiltrating proinflammatory cells and cytokines in the early period initially following BLM exposure and an increase in the tissue-infiltrating suppressive immune cells and factors during the later period following BLM exposure. TLR2 deficiency, however, reduced pulmonary inflammation, injury, and subsequently attenuated pulmonary fibrosis. Targeting TLR2 by a TLR2-neutralizing Ab not only markedly decreased animal death but also protected animals from the development of pulmonary fibrosis and reversed the established pulmonary fibrosis through regulating BLM-induced immunosuppressive microenvironments. Our studies suggest that TLR2 is a promising target for the development of therapeutic agents against pulmonary fibrosis and that eliminating immunosuppressive cells and factors via immunostimulants is a novel strategy for fibro-proliferative diseases. Moreover, combining BLM with an anti-TLR2 Ab or TLR2 antagonist for cancer therapy will improve the BLM therapeutic profile by enhancing anti-cancer efficacy and reducing systemic inflammation and pulmonary fibrosis.

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Section: Discussionmentioning

confidence: 99%

Targeting TLR2 Attenuates Pulmonary Inflammation and Fibrosis by Reversion of Suppressive Immune Microenvironment

Yang

Cui

Liu

et al. 2009

The Journal of Immunology

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“…Major targets of most TLR ligands are the myeloid cells, including macrophages and DCs [33][34][35][36]. It has been reported that several distinct TLR ligands are capable of inducing the expression of 1α-hydroxylase in human monocytes and macrophages [13,16].…”

Section: Subcutaneously Administered Tlr Ligands That Induce Increasementioning

confidence: 99%

TLR ligands that stimulate the metabolism of vitamin D3 in activated murine dendritic cells can function as effective mucosal adjuvants to subcutaneously administered vaccines

Enioutina

Bareyan

Daynes

2008

Vaccine

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Cathelicidin production by human myeloid cells stimulated through toll like receptor (TLR) 2/1, the migration of human CD8 + T cells to inflamed skin sites, and the ability of murine dendritic cells (DCs) to migrate from skin sites of vaccination to mucosal lymphoid organs all occur via calcitrioldependent mechanisms. Herein, we report that murine DCs exposed to TLR3/TLR4 ligands upregulate their expression of 1α-hydroxylase, the enzyme that converts circulating 25(OH)D 3 to calcitriol, the active form of vitamin D3. TLR3/TLR4 ligands injected subcutaneously affect DC migration in vivo, allowing their trafficking to both draining and non-draining systemic and mucosal lymphoid organs. Subcutaneously delivered vaccines containing TLR3/TLR4 ligands and antigen stimulate the induction of both systemic and mucosal immune responses. Vaccines containing TLR9 ligands fail to stimulate 1α-hydroxylase protein expression, are incapable of redirecting DC migration into Peyer's patches and do not induce mucosal immune responses. These findings support a hypothesis that active metabolites of vitamin D3 produced locally are able to affect various aspects of innate and acquired immune responses. Keywords dendritic cells; TLR ligands; mucosal immune response; calcitriol IntroductionIn mammals there are at least 12 members of the toll like receptor (TLR) family. These receptors not only recognize a number of specific components conserved among microorganisms, but are also capable of recognizing specific defensins as well as fragments of extracellular matrix proteins [1][2][3][4][5][6][7]. Since, the activation of macrophages or dendritic cells (DCs) through one or more of their TLRs enhances innate immunity and can modulate the subsequent development of antigen-specific adaptive immunity, some TLR ligands have been used as adjuvants in vaccine formulations administered parenterally to augment systemic immune responses [8][9][10][11]. Specific TLR ligands have been reported to promote the induction of both systemic and mucosal immune responses when co-administered with antigen intranasally [9][10][11][12].*Corresponding author. Address: Department of Pathology, University of Utah Medical School, 30 North 1900 East, Salt Lake City, UT 84132, USA; Phone: 1-801-585-1522; Fax: 1-801-581-8946; e-mail: elena.enioutina@path.utah.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access Author ManuscriptVaccine. Author manuscript; available in PMC 2009 January 30. Published in final edited form as:Vaccine. We have previously demonstrated that the subcutaneous or intradermal imm...

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“…However, the Dectin-1 mAb interfered with the induction of DNA synthesis by Sophy β-glucan in the PBMCs and also prevented the upregulation of IL-8 production by the U937 cells. In general, β-glucans bind to Dectin-1 while interacting with TLRs, especially TLR-2, to activate the MyD88 adaptor (2,13,36,43). As a result, NF-κB is activated to induce the production of the inflammatory cytokines IL-1, IL-6, IL-8, IL-12, IL-18 and TNF-α, and also the expression of co-stimulatory molecules (20).…”

Section: Immunological Actions Of Sophy β-Glucanmentioning

confidence: 99%

Immunological Actions of Sophy β‐Glucan (β‐1,3‐1,6 Glucan), Currently Available Commercially as a Health Food Supplement

Ikewaki

Fujii²,

Onaka³

et al. 2007

Microbiology and Immunology

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-4). In these blocking experiments using the mAbs, the main differences in the results between PBMCs and U937 cells were that the mAbs against TLR-2 and TLR-4 did not block the Sophy ␤-glucan-induced production of IL-8 in the U937 cells. Furthermore, a mAb to the ␤-glucan receptor, Dectin-1, significantly (P<0.05) blocked the Sophy ␤-glucaninduced DNA synthesis in the PBMCs, and Sophy ␤-glucan-induced production of IL-8 in the U937 cells. The Sophy ␤-glucan-induced production of IL-8 in the U937 cells was significantly (P<0.01) blocked by the conventional protein kinase C (PKC) inhibitor Go6976, the novel PKC inhibitor Rottlerin, the protein kinase A (PKA) inhibitor H-89, and the protein tyrosine kinase (PTK) inhibitor herbimycin A. Among these, the blocking effect of the novel PKC (PKC delta isoenzyme) inhibitor Rottlerin was the most pronounced. Studies employing reverse transcriptase-polymerase chain reaction (RT-PCR) showed that Sophy ␤-glucan stimulated the expression of IL-8 mRNA in the U937 cells, and that this induction was inhibited by Rottlerin. Sophy ␤-glucan also blocked the stimulator cell induction of DNA synthesis and IFN-␥ production in the responder cells in a one-way mixed lymphocyte reaction (MLR) using allogenic PBMCs. Interestingly, immunoglobulin G (IgG), but not IgM to Sophy ␤-glucan was detected in the sera derived from normal adult donors and from the umbilical cord blood of neonates. Taken together, these findings strongly suggest that the Sophy ␤-glucan may have unique immune regulatory or enhancing properties that could be exploited by the health food, medical and pharmaceutical industries.

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Toll-Like Receptor Signaling Mechanisms Involved in Dendritic Cell Activation: Potential Therapeutic Control of T Cell Polarization

Cited by 48 publications

References 88 publications

Targeting TLR2 Attenuates Pulmonary Inflammation and Fibrosis by Reversion of Suppressive Immune Microenvironment

Targeting TLR2 Attenuates Pulmonary Inflammation and Fibrosis by Reversion of Suppressive Immune Microenvironment

TLR ligands that stimulate the metabolism of vitamin D3 in activated murine dendritic cells can function as effective mucosal adjuvants to subcutaneously administered vaccines

Immunological Actions of Sophy β‐Glucan (β‐1,3‐1,6 Glucan), Currently Available Commercially as a Health Food Supplement

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