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- Title
INNATE IMMUNE RESPONSE TO FUNGAL β-GLUCANS VIA THE SPECIFIC CELL SURFACE RECEPTOR DECTIN-1.
- Authors
Adachi, Yoshiyuki
- Abstract
INTRODUCTION Dectin-1 is a specific receptor for 1,3-/β glucans which is expressed on various kinds of leukocytes, such as macrophages, neutrophils, and dendritic cells. It plays an important role for activating innate immune response to fungal infection and functions as a signaling receptor for the activation of superoxide production and inflammatory gene expression by the NF-κB-activation pathway. There is a need to further characterize the stimulator), 1,3-β-glucan agonists for Dectin- 1 in view of the diversity of the various physicochemical properties of 1,3-β-glucans such as branching ratio, length of branched glucosyl residues, degree of polymerization of main glucosyl chain and solubility. In terms of branching structure 1,3-β-glucans may be dassifled into three major groups: (1) a monoglucosyl branched linear 1,3-β-glucan as represented by Sonifilan (SPG), a soluble glucan obtained from liquid-cultured extracellular polysaccharide of Schizophyllum connnune. (2) Tree-like branched main 1,3-glucosyl linkage with 1,6-monoglucosyl branched 1,3-β-glucans as represented by Lentinan and SCG, which are extracted from the fruit body of edible mushrooms. (3) a linear 1,3-β-glucan with various lengths of the 1,6-glucosyl chain as represented by CSBG and OX-CA from yeast (Candida allmans) or Zymosan (Saccharomyces cerevisiae). In this study, we used several structurally defined and physicochemical different 1,3-β-glucans and evaluated innate immune responses such as NF-κB activation and cytokine production from Dectin-1-expressing cells. RESULTS AND DISCUSSION Molecular mechanisms for 1,3-β-glucan recognition and NFκB activation in Dectin-1-transfectant Zymosan has been used as a model compound of yeast microorganisms and stimulates macrophages mainly through TLR2- and Dectin-1-mediated recognition. In order to examine the contribution of Dectin-1 in TLR2/MyD88- mediated NF-κB activation, various Dectin-1 mutants were tested in TLR2 coexpressed HE293 transfectant. The NF-κB activation in TLR2 transfectant was significantly enhanced by coexpression of wild-type Dectin-1. The Dectin-1 mutants, in which amino acid residues of extracellular Trp221 and His223 (carbohydrate recognition domain) or intracellular Tyr15 (ITAM motif) are replaced with alanine or phenylalanine, had a lower activation of NF-κB. This is comparable to TLR2-alone-expressed HEK293 [ 1 ]. However, wild-type Dectin-1 transfectant without TLR2 did not respond to stimulation with Zymosan. In the case of stimu lation of Dectin-l/TLR2 coexpressed HEK293 transfectant with purified particulate 1,3-/β-glucan (OX-CA), the cell showed no activation of NF-κB. These results indicate that Dectin-1 functions as a costimulatory signaling receptor for TLR2-mediated NF-κB activation in HEK293, and Zymosan may have multiple agonist effects, not only as β-glucan, but also involving TLR2 reactive ligands. Structure-activity relationship on Dectin-1/Card9-mediated NF-κB activation Card9 is newly identified signaling molecule in innate immune response and mediates Dectin-1-related NF-&kapp;B activation. To examine which type of 1,3-/β-glucan can stimulate the Dectin-1/Card9/Bcl10 signaling pathway, various 1,3-β-glucans were tested, using Dectin-1/Card9/Bcl10 expressing HEK293T transfectant. Incubation of the cells with Zymosan and OX-CA showed enhanced NF-κB activation, but CSBG (the soluble form of OX-CA), SCG, and SPG did not increase the NF-κB-assisted luciferase expression [2]. These resuhs suggest that the particulate form of 1,3-β-glucan stinm lates Dectin-1/Card9/Bcl10 signaling, and that this activation pathway does not require TLR2-reactive ligands. Innate immune response to soluble 1,3-β-glucans in Dectin-1 knockout mice.…
- Subjects
GLUCANS
- Publication
Mediators of Inflammation, 2007, Vol 2007, Issue 2, p4
- ISSN
0962-9351
- Publication type
Abstract