Disease relevance of CHI3L1

• Elevated levels of CHI3L1 (chitinase-3-like protein 1) are associated with disorders exhibiting increased connective tissue turnover, such as rheumatoid arthritis, osteoarthritis, scleroderma, and cirrhosis of the liver [1].
• High levels of serum HER-2/neu and YKL-40 independently reflect aggressiveness of metastatic breast cancer [2].
• In multivariate Cox analysis, high serum levels of HER2 or YKL-40 or lack of estrogen receptors independently doubled the relative risk of progression and dying (P < 0.001) even after accounting for other independent prognostic variables, such as axillary nodal involvement at primary diagnosis, liver metastases, and more than two metastatic sites [2].
• Increased levels of HC-gp39 have been demonstrated in synovial fluids of patients with rheumatoid or osteoarthritis [3].
• The expression of the TM markers, MGP and CHI3L1, was examined using recombinant adenoviruses containing the respective promoters [4].
• YKL-40 and MMP-9 can be monitored in patients' serum and help confirm the absence of active disease in GBM and YKL-40 in anaplastic glioma patients [5].
• CHI3L1 -131G-->C genotype was strongly associated with the stage of liver fibrosis in the screening (n=265, P=0.001) and validation cohort (n=175, P=0.009) [6].

High impact information on CHI3L1

• The expression of CHI3L1 protein clearly was detectable in lamina propria and colonic epithelial cells (CECs) in several murine colitis models and ulcerative colitis and Crohn's disease patients but absent in normal controls [7].
• CONCLUSIONS: CHI3L1 plays a pathogenic role in colitis, presumably by enhancing the adhesion and invasion of bacteria on/into CEC [7].
• RESULTS: Microarray analysis identified that CHI3L1 is up-regulated specifically in inflamed mucosa [7].
• The gentamicin protection assays using intracellular bacteria showed that CHI3L1 is required for the enhancement of adhesion and internalization of these bacteria in CEC [7].
• Chitinase 3-like-1 (CHI3L1) messenger RNA and protein expressions were examined by reverse-transcription polymerase chain reaction and immunohistochemistry [7].

Chemical compound and disease context of CHI3L1

• A gentamicin protection assay of Salmonella typhimurium was performed using epithelial cell lines that are engineered genetically to overexpress or lack mouse CHI3L1 [7].
• To examine the functional role of CHI3L1 in vivo, anti-CHI3L1 antibody was administered into the dextran sulfate sodium colitis model [7].
• METHODS: Serum YKL-40 was determined by radioimmunoassay in 19 patients with GCA and 8 patients with polymyalgia rheumatica (PMR) who were followed up prospectively during 1 year of treatment with prednisolone [8].
• METHODS: Liver biopsy scored by the Ishak method was compared to biochemical tests, platelet count and two fibrosis biomarkers: hyaluronic acid (HA) and YKL-40 [9].
• YKL-40 (p=0.04) and aspartate aminotransferase (p=0.05) remained associated with steatosis after controlling for fibrosis [9].

Biological context of CHI3L1

• Thus HC-gp39 initiates a signalling cascade in connective-tissue cells which leads to increased cell proliferation, suggesting that this protein could play a major role in the pathological conditions leading to tissue fibrosis [3].
• Phosphorylation of both extracellular signal-regulated kinases 1/2 and AKT occurred in a dose- and time-dependent fashion upon addition of HC-gp39 [3].
• To allow further investigations of its unique expression pattern and to facilitate studies on the regulation of this "marker gene," we characterized the genomic organization of the HC gp-39 gene (HGMW-approved symbol CHI3L1) and cloned its 5'-proximal promotor region [10].
• In contrast, the protective TTG haplotype was associated with a high level of CHI3L1 expression [11].
• Third, we found that an allele of SNP4 (rs4950928), the tagging SNP of CCC, impaired the MYC/MAX-regulated transcriptional activation of CHI3L1 by altering the transcriptional-factor consensus sequences, and this may be responsible for the decreased expression of the CCC haplotype [11].

Anatomical context of CHI3L1

• Thus, induction and continued secretion of CHI3L1 in chondrocytes require sustained activation of NF-kappaB [1].
• Selective induction of CHI3L1 by cytokines acting through NF-kappaB coupled with the known restriction of the catabolic responses by CHI3L1 in response to these inflammatory cytokines represents a key regulatory feedback process in controlling connective tissue turnover [1].
• gp38k (CHI3L1) is a secreted heparin-binding glycoprotein whose expression, in vitro, is associated with vascular smooth muscle cell (VSMC) migration and invasion into the underlying gelatinous matrix. gp38k is expressed at high levels in postconfluent "nodular" VSMC cultures and at low levels in subconfluent proliferating cultures [12].
• We report here that HC-gp39 promotes the growth of human synovial cells as well as skin and fetal lung fibroblasts [3].
• A dose-dependent growth stimulation was observed when each of the fibroblastic cell lines was exposed to HC-gp39 in a concentration range from 0.1 to 2 nM, which is similar to the effective dose of the well-characterized mitogen, insulin-like growth factor-1 [3].

Associations of CHI3L1 with chemical compounds

• In these patients, high serum YKL-40 was a stronger predictor of survival than high serum HER2 or lack of estrogen receptors [2].
• Functional Variants in the Promoter Region of Chitinase 3-Like 1 (CHI3L1) and Susceptibility to Schizophrenia [11].
• In contrast, expression of YKL-40 was induced by IFNgamma and suppressed by dexamethasone [13].
• In contrast to YKL-40, YKL-39 is not a glycoprotein and does not bind to heparin [14].
• Furthermore, HC gp-39 expression levels correlate with the degree of morphological differentiation induced by PMA and vitamin D3 treatments [15].
• Serial monitoring of serum PINP, BAP, CTX-I, and YKL-40 in metastatic PC patients during hormonal treatment provided information of prognosis [16].

Physical interactions of CHI3L1

• SpA synovitis was characterized by higher vascularity and infiltration with CD163+ macrophages and polymorphonuclear leukocytes (PMNs) and by lower values for lining-layer hyperplasia, lymphoid aggregates, CD1a+ cells, intracellular citrullinated proteins, and MHC-HC gp39 complexes than RA synovitis [17].

Co-localisations of CHI3L1

• YKL-40 was found to colocalize and comobilize with lactoferrin (the most abundant protein of specific granules) but not with gelatinase in subcellular fractionation studies on stimulated and unstimulated neutrophils [18].

Regulatory relationships of CHI3L1

• In neonatal rat chondrocytes, the inflammatory cytokines tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 potently induced steady-state levels of CHI3L1 mRNA and protein secretion [1].
• Moreover, CD4(+) T cell lines directed against HC gp-39 expressed CD25, glucocorticoid-induced tumor necrosis factor receptor, and Foxp3 molecules and were capable of suppressing antigen-specific T cell responses [19].
• HC-gp39 contributes to chondrocyte differentiation by inducing SOX9 and type II collagen expressions [20].
• In contrast, both basic fibroblast growth factor and tumor necrosing factor-alpha repressed YKL-40 [21].
• CONCLUSION: T cell epitopes of HCgp-39 that were defined in HLA-DR4 transgenic mice stimulated T cells from human subjects carrying RA-associated HLA-DR4 alleles [22].

Other interactions of CHI3L1

• Enhanced levels of YKL-40 may, therefore, be derived from synovial cells while modulation of YKL-39 and collagen 2 expression reflected the cartilage metabolism in response to degradation [23].
• The use of selective inhibitors of the mitogen-activated protein kinase and the protein kinase B (AKT) signalling pathways indicates that both are involved in mediating the mitogenic response to HC-gp39 [3].
• We have previously reported that the expression of HC gp-39, a 39-kDa secretory glycoprotein and member of the chitinase protein family, is associated with late stages of monocyte to macrophage maturation [10].
• YKL-40 mRNA transcripts were detected by in situ hybridization in 9 of 10 biopsies from SCLC patients, and in each case the signal was localized in the peritumoral stroma in cells of typical macrophage morphology (confirmed by a CD68 macrophage specific stain) [24].
• The suppressive effects of HC-gp39 were dependent on phosphoinositide 3-kinase activity, and treatment of cells with HC-gp39 resulted in AKT-mediated serine/threonine phosphorylation of apoptosis signal-regulating kinase 1 [25].

Analytical, diagnostic and therapeutic context of CHI3L1

• Fewer patients with high serum HER2 or YKL-40 or lack of estrogen receptors responded with a complete remission on chemotherapy (P = 0.005, 0.036, and 0.006) [2].
• In the present study, we used immunohistochemistry to investigate YKL-40 protein expression in independent sets of glioblastomas and anaplastic oligodendrogliomas to determine whether this single marker can aid classification of these high-grade gliomas [26].
• YKL-40 expression was also compared with genetically defined subsets of glioblastoma by assessing epidermal growth factor receptor amplification and loss at chromosome 10q, two of the common recurring aberrations in these tumors, using fluorescent in situ hybridization [27].
• YKL-40, a matrix protein of specific granules in neutrophils, is elevated in serum of patients with community-acquired pneumonia requiring hospitalization [28].
• METHODS: Serum YKL-40 was determined by radioimmunoassay in 156 patients with RA during a 1 yr longitudinal study [29].

References