Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P80098 (monocyte chemoattractant protein)
 1,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The protein human CC chemokine ligand 2 (CCL2, also known as monocyte chemoattractant protein 1 or MCP-1) has been synthesized using a combination of solid phase peptide synthesis (SPPS) and native chemical ligation (NCL). The thioester-peptide segment was synthesized using the sulfonamide safety-catch linker and 9-fluorenylmethoxycarbonyl (Fmoc) SPPS, and pseudoproline dipeptides were used to facilitate the synthesis of both CCL2 fragments. After assembly of the full-length peptide chain by NCL, a glutathione redox buffer was used to fold and oxidize the CCL2 protein. Synthetic human CCL2 binds to and activates the CCR2 receptor on THP-1 cells, as expected. CCL2 was crystallized and the structure was determined by X-ray diffraction at 1.9-A resolution. The structure of the synthetic protein is very similar to that of a previously reported structure of recombinant human CCL2, although the crystal form is different. The functional CCL2 dimer for the crystal structure reported here is formed around a crystallographic twofold axis. The dimer interface involves residues Val9-Thr10-Cys11, which form an intersubunit antiparallel beta-sheet. Comparison of the CCL2 dimers in different crystal forms indicates a significant flexibility of the quaternary structure. To our knowledge, this is one of the first crystal structures of a protein prepared using the sulfonamide safety-catch linker and NCL.
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PMID:Synthesis by native chemical ligation and crystal structure of human CCL2. 2009 76

Autoimmune diseases represent one of the most challenging clinical entities with unmet medical needs, so the continued development of novel therapeutics is well justified. Most autoimmune diseases are marked by the infiltration of lymphomyeloid cells in target tissues, leading to inflammation and tissue damage. This process is guided by chemokines that act as signaling bridges amidst a complex network of immune cells. For example, monocytes are believed to be the primary cell type responsible for pathology initiation and tissue damage, while T lymphocytes are thought to orchestrate the process by secreting more cytokines/chemokines to amplify leukocyte homing. Many studies have addressed the molecular basis of monocyte recruitment in different autoimmune diseases, and the conclusions pointed to a major role played by monocyte chemoattractant protein 1 (MCP-1), also known as CC chemokine ligand 2 (CCL2), and its cell-surface receptor, CC chemokine receptor (CCR) 2. These findings suggest that by interfering with CCL2 or its receptor, it is possible to inhibit the progression of CCR2-dependent diseases. Therefore, future therapy design targeting a maladapted immune response could target chemokine receptors starting with the CCL2-CCR2 axis.
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PMID:A CCL2-based fusokine as a novel biopharmaceutical for the treatment of CCR2-driven autoimmune diseases. 2108 26

Mouse CCL8 is a CC chemokine of the monocyte chemoattractant protein (MCP) family whose biological activity and receptor usage have remained elusive. Here we show that CCL8 is highly expressed in the skin, where it serves as an agonist for the chemokine receptor CCR8 but not for CCR2. This distinguishes CCL8 from all other MCP chemokines. CCL8 responsiveness defined a population of highly differentiated, CCR8-expressing inflammatory T helper type 2 (T(H)2) cells enriched for interleukin (IL)-5. Ccr8- and Ccl8-deficient mice had markedly less eosinophilic inflammation than wild-type or Ccr4-deficient mice in a model of chronic atopic dermatitis. Adoptive transfer studies established CCR8 as a key regulator of T(H)2 cell recruitment into allergen-inflamed skin. In humans, CCR8 expression also defined an IL-5-enriched T(H)2 cell subset. The CCL8-CCR8 chemokine axis is therefore a crucial regulator of T(H)2 cell homing that drives IL-5-mediated chronic allergic inflammation.
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PMID:Mouse CCL8, a CCR8 agonist, promotes atopic dermatitis by recruiting IL-5+ T(H)2 cells. 2124 98

CC chemokine ligand-2 (CCL2)/monocyte chemoattractant protein (MCP)-1 expression is upregulated during pulmonary inflammation, and the CCL2-CCR2 axis plays a critical role in leukocyte recruitment and promotion of host defense against infection. The role of CCL2 in mediating macrophage subpopulations in the pathobiology of noninfectious lung injury is unknown. The goal of this study was to examine the role of CCL2 in noninfectious acute lung injury. Our results show that lung-specific overexpression of CCL2 protected mice from bleomycin-induced lung injury, characterized by significantly reduced mortality, reduced neutrophil accumulation, and decreased accumulation of the inflammatory mediators IL-6, CXCL2 (macrophage inflammatory protein-2), and CXCL1 (keratinocyte-derived chemokine). There were dramatic increases in the recruitment of myosin heavy chain (MHC) II IA/IE(int)CD11c(int) cells, exudative macrophages, and dendritic cells in Ccl2 transgenic mouse lungs both at baseline and after bleomycin treatment compared with levels in wild-type mice. We further demonstrated that MHCII IA/IE(int)CD11c(int) cells engulfed apoptotic cells during acute lung injury. Our data suggested a previously undiscovered role for MHCII IA/IE(int)CD11c(int) cells in apoptotic cell clearance and inflammation resolution.
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PMID:A macrophage subpopulation recruited by CC chemokine ligand-2 clears apoptotic cells in noninfectious lung injury. 2228 13

The CC chemokine monocyte chemoattractant protein (MCP)-1/CCL2 is involved in the formation, progression, and destabilization of atheromatous plaques and plays an essential role in postinfarction remodeling. The aim of the present study was to evaluate the role of MCP-1 gene polymorphisms as susceptibility markers for premature coronary artery disease (CAD) and cardiovascular risk factors in the Mexican population. Four MCP-1 gene polymorphisms (rs1024611, rs2857654, rs3760396, and rs1024610) were genotyped by 5' exonuclease TaqMan assays in a group of 1072 patients with premature CAD, and 1082 healthy unrelated controls (with negative calcium score by computed tomography) seeking for associations with premature CAD and other metabolic and cardiovascular risk factors using logistic regression analyses. MCP-1 polymorphism frequencies were similar in premature CAD patients and healthy controls. When the analysis included only those premature CAD patients without type 2 diabetes mellitus (T2DM), the rs1024610 polymorphism was associated with increased risk of developing premature CAD under dominant and additive models adjusted by age and gender (OR=1.33, Pdom=0.040 and OR=1.34, Padd=0.027). The effect of the MCP-1 polymorphisms on various metabolic cardiovascular risk factors and metabolic parameters was explored separately in controls, and premature CAD. In this analysis adjusted by age and gender, the rs3760396 CC genotype was associated with low levels of gamma-glutamyl transpeptidase (P=0.002), whereas, the rs1024610 TT genotype was associated with decreased risk of T2DM (P=0.035) in premature CAD patients. One haplotype (CATG) was associated with increased risk of developing premature CAD (OR=1.44, P=0.0019). In summary, in our study, the rs1024610 polymorphism was associated with increased risk of developing premature CAD only in those patients without T2DM. The four MCP-1 polymorphisms were in high linkage disequilibrium and one haplotype was significantly associated with risk of developing premature CAD.
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PMID:Monocyte chemoattractant protein-1 gene (MCP-1) polymorphisms are associated with risk of premature coronary artery disease in Mexican patients from the Genetics of Atherosclerotic Disease (GEA) study. 2627 53

Sepsis is a systemic host response to infection, and patients with sepsis are frequently handled in the intensive care unit. However, mortality related to sepsis remains high throughout the world. In addition, there have been no efficient prognostic biomarkers for sepsis to be employed in clinical practice. We therefore aimed to identify prognostic biomarkers for sepsis using the chemokine/cytokine array. This study included 143 patients with sepsis, who were divided into survivor and nonsurvivor groups according to their 28-day mortality status. The cytokine array analysis was performed with plasma samples from two randomly selected patients in each sepsiofgroup. We thus identified seven cytokines with significantly and consistently different expression levels between nonsurvivors and survivors. The validity of the selected cytokines was then assessed by enzyme-linked immunosorbent assay (ELISA). We finally found monocyte chemoattractant protein 1 (MCP-1) as the most useful biomarker to distinguish the two sepsis groups; namely, non-surviving patients (n = 56) exhibited significantly higher plasma concentrations of MCP-1 compared to survivors (n = 87). MCP-1 is a CC chemokine, a potent chemoattractant that contributes to systemic inflammatory response syndrome. Areas under the receiver operating characteristic curves for prediction of 28-day mortality were 0.763 for MCP-1, 0.680 for the Acute Physiologic Assessment and Chronic Health Evaluation II (APACHE II) score, 0.64 for the Sequential Organ Failure Assessment (SOFA) score, 0.621 for procalcitonin, and 0.785 for MCP-1 plus APACHE II score. In conclusion, we propose that plasma MCP-1 is a useful biomarker in predicting outcome of sepsis.
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PMID:Plasma Monocyte Chemoattractant Protein 1 as a Predictive Marker for Sepsis Prognosis: A Prospective Cohort Study. 2820 56

The regenerative capacity of peripheral nerves declines during aging, contributing to the development of neuropathies, limiting organism function. Changes in Schwann cells prompt failures in instructing maintenance and regeneration of aging nerves; molecular mechanisms of which have yet to be delineated. Here, we identified an altered inflammatory environment leading to a defective Schwann cell response, as an underlying mechanism of impaired nerve regeneration during aging. Chronic inflammation was detected in intact uninjured old nerves, characterized by increased macrophage infiltration and raised levels of monocyte chemoattractant protein 1 (MCP1) and CC chemokine ligand 11 (CCL11). Schwann cells in the old nerves appeared partially dedifferentiated, accompanied by an activated repair program independent of injury. Upon sciatic nerve injury, an initial delayed immune response was followed by a persistent hyperinflammatory state accompanied by a diminished repair process. As a contributing factor to nerve aging, we showed that CCL11 interfered with Schwann cell differentiation in vitro and in vivo. Our results indicate that increased infiltration of macrophages and inflammatory signals diminish regenerative capacity of aging nerves by altering Schwann cell behavior. The study identifies CCL11 as a promising target for anti-inflammatory therapies aiming to improve nerve regeneration in old age.
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PMID:Inflammaging impairs peripheral nerve maintenance and regeneration. 3016 37


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