Disease relevance of CCL2

• Supernatants of neuroblastoma cell lines that produced CCL2 induced in vitro migration of iNKTs from blood of patients and normal adults; this was abrogated by an anti-CCL2 monoclonal antibody [1].
• Serum levels of CCL2 in pancreatic cancer patients were significantly higher than in normal healthy subjects (P < 0.0001) [2].
• The role of MCP-1 (CCL2) and CCR2 in multiple sclerosis and experimental autoimmune encephalomyelitis (EAE) [3].
• Evidence from descriptive, transgenic, knockout and neutralizing studies of experimental autoimmune encephalomyelitis (EAE) points towards a nonredundant role of CCL2 and CCR2 in the recruitment of inflammatory infiltrate into the CNS [3].
• CCL2 has been implicated in macrophage infiltration into the central nervous system and is involved in demyelination in many experimental models of demyelination [4].
• Monocyte chemotactic protein-1 is thus a therapeutic target, and may represent an important factor linking adipose tissue inflammation, obesity and type 2 diabetes [5].
• These observations demonstrate similar interstitial concentrations and a differential gene response to hyperinsulinemia of MCP-1 in the SCAAT from L and OB individuals [6].
• MCP-1 SNP-2518 may be a valuable genetic marker for assessing the risk of developing distant metastasis after the radiotherapy in NPC patients [7].

Psychiatry related information on CCL2

• Increased central nervous system (CNS) levels of monocyte chemoattractant protein 1 [CC chemokine ligand 2 (CCL2) in the systematic nomenclature] have been reported in chronic neurological diseases such as human immunodeficiency virus type 1-associated dementia, amyotrophic lateral sclerosis, and multiple sclerosis [8].
• No evidence for association of the monocyte chemoattractant protein-1 (-2518) gene polymorphism and Alzheimer's disease [9].
• No relationship was observed between chemokine levels and atherosclerosis risk factors (hypertension, diabetes, smoking, and alcohol consumption), and MCP-1 was also not related to age or gender [10].

High impact information on CCL2

• In studies of function, lung T cells from patients with sarcoidosis and high-intensity alveolitis released monocyte chemotactic factor (a lymphokine critical to granuloma formation) and polyclonally activated B cells to produce immunoglobulins [11].
• The accumulation of monocytes in the lung in patients with pulmonary sarcoidosis may be mediated by local production of monocyte chemotactic factor by lung T lymphocytes [12].
• Although MCP-1 has a powerful effect on monocytes, IL-8 is thought to act predominantly on neutrophils and it is unclear how it could recruit monocytes [13].
• MCP-1 and IL-8 trigger firm adhesion of monocytes to vascular endothelium under flow conditions [13].
• These data reveal a role for MCP-1 in the development of early atherosclerotic lesions and suggest that upregulation of this chemokine by minimally oxidized lipids is an important link between hyperlipidaemia and fatty streak formation [14].

Chemical compound and disease context of CCL2

• Chemokines in the MPTP model of Parkinson's disease: Absence of CCL2 and its receptor CCR2 does not protect against striatal neurodegeneration [15].
• Steroid therapy altered serum levels of CCL2 and CCL5 chemokines in multiple sclerosis patients during relapse [16].
• Monocyte and lymphocyte targeting chemokines appear to play a role in caprine arthritis encephalitis (CCL2) and canine endotoxemia (CXCL10) [17].
• In response to LPS stimulation, patients with pulmonary tuberculosis showed increased CCL2 and TNFalpha responses as compared with the extra-pulmonary group [18].
• Moreover, Cy superinduced MCP gene expression in cells other than monocytes, including endothelial cells, smooth muscle cell and fibrosarcoma cells, indicating different mechanisms of regulation in mononuclear phagocytes vs cells of other lineages [19].

Biological context of CCL2

• A direct effect of CCL2 on tumor cells is to be excluded, either because primary tumors as well as cell lines have no detectable CCL2 receptor (CCR2) and because addition of CCL2 on tumor cells in vitro did not modify cell cycle progression or apoptosis [2].
• Up-regulation of E-selectin and CCL2 by the killed bacteria was not inhibited by polymyxin B [20].
• Finally, dimerization of MT1-MMP was found to be enhanced by CCL2 in ECs in a PI3K- and actin polymerization-dependent manner [21].
• As a functional correlate, chemotaxis assays using the CCR2 ligand, CCL2 (MCP-1), were performed [22].
• Conditioned medium from M. tuberculosis-infected osteoblasts (COBTB) drives CXCL8 and some CCL2 gene expression and secretion from primary human monocytes [23].

Anatomical context of CCL2

• Ligation of the chemokine receptor CCR2 on monocytes and macrophages with its ligand CCL2 results in activation of the cascade consisting of phosphatidylinositol-3-OH kinase (PI(3)K), the small G protein Rac and lamellipodium protrusion [24].
• CCR2, the receptor for CCL2, was more frequently expressed by iNKT compared with natural killer and T cells from blood (P < 0.001) [1].
• This hypothesis was supported by findings that MIF induced CCL2 release from primary microvascular endothelial cells [25].
• Double labeling confirmed up-regulation of CCL2/CCR2 on myofibroblasts, pericytes, lymphocytes, macrophages, and endothelial cells [26].
• CCR2 expression on SSc fibroblasts appears to regulate the expression of CCL2 and alpha-SMA [26].

Associations of CCL2 with chemical compounds

• However, the up-regulation of CCL2 mRNA was COX-2-independent but required tyrosine kinase and protein kinase C (PKC) [27].
• PD 98059, fludarabine, piceatannol, and curcumin (AP-1 inhibitor) inhibited the OSM-induced expression of CCL2 [27].
• In NF-kappaB blocking experiments using pyrrolidine dithiocarbamate, CoMTsAg-induced CCL2 secretion was reduced by up to 80% (p = 0.0006), whereas CXCL8 was inhibited by up to 75% (p = 0.0003) [28].
• We found that fMLP, but not C3a or C5a, induced macrophage inflammatory protein (MIP)-1ss (CCL4) and monocyte chemoattractant protein-1 (CCL2) mRNA and protein [29].
• Although the function of CCL2 in the brain is unclear, it is believed that upregulation of this chemokine during neuropathologic or neuroinflammatory conditions leads to recruitment of activated monocytes into the brain, where they differentiate into macrophages producing neurotoxic and inflammatory molecules [30].
• Anti-CCL2 inhibition was not as effective as docetaxel (40 mg/kg, every week for 3 weeks) as a single agent, but inhibition of CCL2 in combination with docetaxel significantly reduced overall tumor burden compared with docetaxel alone, and induced tumor regression relative to initial tumor burden [31].

Physical interactions of CCL2

• MCP-1 binds the chemokine receptor CCR2 [32].
• Desensitization studies indicate that MCP-2 interacts with receptors recognizing MCP-1 as well as RANTES [33].
• Human fibroblasts express functional IL-2 receptors formed by the IL-2R alpha- and beta-chain subunits: association of IL-2 binding with secretion of the monocyte chemoattractant protein-1 [34].
• PURPOSE: The interleukin (IL)-8 promoter possesses a NF-kappa B-binding site with affinity to p50p65 and p65p65 complexes while the monocyte chemoattractant protein (MCP)-1 promoter's NF-kappa B-binding site has exclusive affinity to p50p65 heterodimers [35].
• The cellular effects of MCP-1 are mediated primarily by binding to CC chemokine receptor-2 [36].

Enzymatic interactions of CCL2

• Synergistic enhancement of cytokine-induced human monocyte matrix metalloproteinase-1 by C-reactive protein and oxidized LDL through differential regulation of monocyte chemotactic protein-1 and prostaglandin E2 [37].
• Pyk2 was tyrosine phosphorylated very quickly after stimulation with MCP-1 [38].
• We found that Lyn, Shc and paxillin were also tyrosine phosphorylated by MCP-1 [38].

Regulatory relationships of CCL2

• In summary, iNKTs migrate toward neuroblastoma cells in a CCL2-dependent manner, preferentially infiltrating MYCN nonamplified tumors that express CCL2 [1].
• In this report, we show that MCP-1 binding to the CCR2 receptor in Mono Mac 1 cells promotes the rapid desensitization of MCP-1-induced calcium flux responses [39].
• RANTES was expressed almost exclusively by T cells whereas the expression of MCP-1, MIP-1alpha, and MIP-1beta was confined largely to macrophages [40].
• Binding studies showed that eotaxin displaces (125) I-MCP-1 from monocytes in a concentration-dependent manner, and functional experiments showed that eotaxin inhibits MCP-1-induced chemotaxis and enzyme release [41].
• CONCLUSION: SSc fibroblasts display a specific pattern of chemokine gene expression that is characterized by constitutively increased and abnormally regulated expression of MCP-1 in vitro [42].
• This GM-CSF-induced MCP-1 expression, measured as both protein and mRNA levels, was down-regulated by atorvastatin, a 3-hydroxy-3-methylglutaryl-CoA reductase inhibitor [43].

Other interactions of CCL2

• Here we focus on findings in the CCL2-CCR2 and CCL3-CCR5 ligand-receptor systems [44].
• On these cells, it binds to receptors that recognize MCP-1, MCP-3, and RANTES [45].
• Thus, MCP-3 was as effective as MCP-1 as an inducer of mediator release, and as effective as RANTES as a stimulus of basophil migration [46].
• Human MIP-1 alpha elicited no response in canine dermis, whereas monocyte chemoattractant protein 1 caused mild perivascular cuffing with monocytes [47].
• MCP-4 shares the pyroglutamic acidproline NH2-terminal motif and 56-61% sequence identity with the three known monocyte chemotactic proteins and is 60% identical to eotaxin [45].
• Altogether, these findings indicate that CCL2 protects prostate cancer PC3 cells from autophagic death via the phosphatidylinositol 3-kinase/Akt/survivin pathway and reveal survivin as a critical molecule in this survival mechanism [48].

Analytical, diagnostic and therapeutic context of CCL2

• By immunohistochemistry and in situ hybridization, CCL2 production was confirmed in neoplastic ducts from surgical specimens [2].
• Amounts of CCL2 released into the supernatant were measured by enzyme-linked immunosorbent assay [27].
• METHODS: The expression of messenger RNA (mRNA) for CCL2 and c-Fos was analyzed by Northern blotting [27].
• Transcript expression, confirmed by quantitative real-time PCR analysis for selected genes, was associated with protein induction for some (e.g., CCL2), but not all (e.g., IL-1beta), transcripts examined [49].
• Human pancreatic islets produce and secrete MCP-1/CCL2: relevance in human islet transplantation [50].

References