Abstract
BackgroundCHI3L1 is a chitinase-like protein without enzymatic activity, produced by activated macrophages, chondrocytes, neutrophils. Recent studies on arthritis, asthma, and inflammatory bowel diseases suggest that chitinases are important in inflammatory processes and tissue remodeling, but their production by human T cells, has never been reported.MethodsA microarray analysis of gene expression profile was performed on Th17 and classic Th1 cell clones and CHI3L1 was found among the up-regulated genes on Th17 cells. Different types of helper T cell clones (TCCs) were then evaluated by Real Time PCR (RT-PCR) for CHI3L1 mRNA expression; protein expression was investigated in cell lysates by western blotting and in cultures supernatants by ELISA. ELISA was also used to measure CHI3L1 in the serum and in the synovial fluid (SF) of juvenile idiopathic arthritis (JIA) patients.ResultsAt mRNA level CHI3L1 was highly expressed by Th17, Th17/Th1, non classic Th1 and even in Th17/Th2 cell clones, whereas it was virtually absent in CD161− classic Th1 and Th2 TCCs. CHI3L1 was also detected in cell culture supernatants of Th17 and Th17-derived cells but not of classic Th1. Moreover CHI3L1 was higher in the SF than in serum of JIA patients, and it positively correlated with the frequency of Th17 and non-classic Th1 cells in SF. CHI3L1 in SF also positively correlated with the C reactive protein (CRP) serum levels, and with the levels of some proinflammatory cytokines, such as IL-6 and p40, which is the common subunit of IL12 and IL23.ConclusionsHere we describe for the first time CHI3L1 production by T cells owing the Th17 family. Moreover the positive correlation found between the frequency of Th17 and Th17-derived cell subsets and CHI3L1 levels in SF of JIA patients, in agreement with the suggested role of these cells in inflammatory process, candidates CHI3L1 as a possible biological target in JIA treatment.
Highlights
chitinase 3-like-1 (CHI3L1) is a chitinase-like protein without enzymatic activity, produced by activated macrophages, chondrocytes, neutrophils
CHI3L1 is produced by non‐classic Th1 and Th17 clones In previous studies, we generated a series of classic Th1 and Th17 clones from circulating CD4+ T cells obtained from healthy donors
Among genes that fulfilled the criteria described in the Methods section as up- or down-regulated genes in Th17 versus classic Th1 clones, in addition to those expected on the basis of previous knowledge, such as, RORγt, CCR6, CXCR3, CD161, IL-17, IL-23 receptor (IL-23R) and IL4I1 [40, 41], there was CHI3L1 (Fig. 1a)
Summary
CHI3L1 is a chitinase-like protein without enzymatic activity, produced by activated macrophages, chondrocytes, neutrophils. The majority of the glycosyl 18-hydrolase family member are CLPs and among them chitinase 3-like-1 (CHI3L1) is the most studied: it is endogenously expressed by several cell types including macrophages, neutrophils, chondrocytes, fibroblasts, endothelial cells and colonic, ductal, and airway epithelial cells [1, 8]. CHI3L1 has been shown to stimulate proliferation of human connective tissue cells through a MAPK/ AKT dependent pathway [10] In agreement with these evidences on CHI3L1 activities, KO mice have been generated that developed less severe inflammatory responses at the acute phase of bacterial infectious colitis [11] as well as suppressed Th2-type immune responses, characterized by lower tissue inflammation, fibrosis and higher immune cell apoptosis [9]. As a result of this knowledge CHI3L1 is already considered a prognostic biomarker for several immune mediated diseases and has been proposed to be a therapeutic target in conditions characterized by fibrosis, extracellular matrix remodeling and acute or chronic inflammation [12, 14,15,16]
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