History

Human CCL3 was described as an inhibitor of bone marrow stem-cell proliferation by Lord and coworkers in 1976 [1]. It was identified at the nucleic acid level in 1985 as a 0.98 and 1. 12 kb mRNA doublet that showed rapid differential expression in human peripheral blood mononuclear cells cultured with the lectin, Concanavalin-A, and cycloheximide. The highly selective cDNA cloning procedure had been designed to identify members of a set of putative G0/G1 switch (G0S) regulatory genes, and the gene was named G0S19. Rapid induction was by either Concanavalin-A alone, or by cycloheximide alone [2]. Fuller characterization as part of a family of genes (G0S19-1, G0S19-2 , G0S19-3 and a strange oncogene-associated fragment) was reported in 1990 [3] , 1993 [4], and 1998 [5] .

Disease relevance of CCL3

• CCL3 and CCL4 are natural ligands for the primary human immunodeficiency virus type 1 (HIV-1) coreceptor CCR5 and are also known to activate and enhance the cytotoxicity of natural killer cells [6].
• Genetic variation in the CCL18-CCL3-CCL4 chemokine gene cluster influences HIV Type 1 transmission and AIDS disease progression [6].
• Genomic DNAs from >3,000 participants enrolled in five United States-based natural-history cohorts with acquired immunodeficiency syndrome (AIDS) were genotyped for 21 single-nucleotide polymorphisms (SNPs) in a 47-kb interval on chromosome 17q12 containing the genes CCL3, CCL4, and CCL18 [6].
• CCL3 and CXL10 expression appear to be required for protective NK cell responses in vivo to murine cytomegalovirus or Leishmania major, respectively [7].
• CXCL9, CXCL10, and CCL3 were raised in the CSF in CIDP compared with controls and non-demyelinating neuropathies (p < 0.001) [8].

Psychiatry related information on CCL3

• Low, but detectable, levels of CSF MIP-1alpha were strongly associated with dementia, suggesting that higher levels may have neuroprotective effects [9].

High impact information on CCL3

• The roles of most of these molecules are not well known, although murine MIP-1 alpha of the C-C branch is a specific inhibitor of haematopoietic stem cell proliferation and some members of the C-X-C branch are neutrophil-targeted inflammatory agents [10].
• Identification of RANTES, MIP-1 alpha, and MIP-1 beta as the major HIV-suppressive factors produced by CD8+ T cells [11].
• RANTES, MIP-1 alpha, and MIP-1 beta were released by both immortalized and primary CD8+ T cells [11].
• Two active proteins purified from the culture supernatant of an immortalized CD8+ T cell clone revealed sequence identity with human RANTES and MIP-1 alpha [11].
• Eosinophils also express a much lower level of a second chemokine receptor, CC CKR1, which appears to be responsible for the effects of MIP-1 alpha [12].

Chemical compound and disease context of CCL3

• Moreover, EBV completely down-regulated lipopolysaccharide (LPS)- and phytohemagglutinin-induced MIP-1 alpha production up to 4 hours after induction [13].
• Treatment of marrow stroma with interferon-alpha restores normal beta 1 integrin-dependent adhesion of chronic myelogenous leukemia hematopoietic progenitors. Role of MIP-1 alpha [14].
• We describe the use of MIP-1 alpha in a biotin tyramine-mediated proximity selection to guide the selection of CCR-5-specific phage antibodies from a large phage display human library [15].
• This latter agonist activity appears to be unique to mLPS, since two previously documented LPS antagonists, Rhodobacter sphaeroides diphosphoryl lipid A and synthetic lipid IVA, did not induce MIP-1 alpha and MIP-1 beta secretion [16].

Biological context of CCL3

• First, among AA members of the AIDS Link to the Intravenous Experience cohort of injection drug users, frequencies of three correlated SNPs covering 2,231 bp in CCL3 were significantly elevated among highly exposed, persistently HIV-1-uninfected individuals compared with HIV-1-infected seroconvertors (P = .02-.03) [6].
• Interestingly, FcepsilonRI engagement inhibited CCL3-mediated chemotaxis and membrane ruffling of RBL-CCR1 cells [17].
• CP-481,715 retains activity in human whole blood, inhibiting CCL3-induced CD11b up-regulation and actin polymerization (IC50 = 165 and 57 nm, respectively) on monocytes [18].
• Radiolabeled binding studies indicate that CP-481,715 binds to human CCR1 with a Kd of 9.2 nm and displaces 125I-labeled CCL3 from CCR1-transfected cells with an IC50 of 74 nm [18].
• Our findings suggest that infants who display a deficient-production phenotype of CCL3 are at increased risk of acquiring HIV-1, indicating that this chemokine in particular plays an essential role in protective immunity [19].

Anatomical context of CCL3

• Human memory CD4(+) T cells respond better to inflammatory CCLs/CC chemokines, CCL3 and CCL5, than naive CD4(+) T cells [20].
• Activated lymphocytes synthesize and secrete substantial amounts of the beta-chemokines macrophage inflammatory protein (MIP)-1 alpha/CCL3 and MIP-1 beta/CCL4, both of which inhibit infection of cells with human immunodeficiency virus type 1 (HIV-1) [21].
• CCL3 (MIP-1alpha), a prototype of CC chemokines, is a potent chemoattractant toward human neutrophils pre-treated with GM-CSF for 15 min [22].
• It was observed that mitogen-induced production of CCL3 and CCL4 by cord-blood mononuclear cells was increased among infants born to HIV-positive compared with HIV-negative mothers, and that a deficiency in production of CCL3 was associated with increased susceptibility to intrapartum HIV-1 infection [19].
• Differential pattern of CCR1 internalization in human eosinophils: prolonged internalization by CCL5 in contrast to CCL3 [23].

Associations of CCL3 with chemical compounds

• Thirty-three point mutants of CCR1 were expressed transiently in L1.2 cells, and the cells were assessed for their capacity to migrate in response to CCL3 in the presence or absence of UCB 35625 [24].
• The CXCL12- and CCL3-induced chemotaxis was also dose-dependently inhibited by AMD3451 [25].
• MPTP treatment resulted in decreased CCL2 expression and increased CCL3 expression in the surviving dopaminergic neurons [26].
• After 24 h, consistent upregulatory effects of all sensitizing compounds on transcript expression of CCL2, CCL3 and CCL4 were observed, whereas SDS (and BC) had no effect [27].
• Both MSU and CPPD increased the secretion of IL-8 by neutrophils in a dose- and time-dependent manner, but had no effect on that of MIP-1 alpha [28].

Physical interactions of CCL3

• The transfectants (YT4/293) showed high affinity binding for 125I-MCP3 in addition to specifically binding 125I-MIP1 alpha and 125I-Rantes [29].
• These results suggest that MCP-1 and RANTES receptors are promiscuously coupled to multiple G proteins in IANK cell membranes and that this coupling is different from MIP-1 alpha receptors, which seem to be coupled to G(s), G(o), and G(z) but not to G(i) [30].
• The present manuscript details the discovery and early fundamental structure-activity relationship studies involving compound 3, a novel hydroxyethylene peptide isostere derived molecule that provides micromolar inhibition of CCL3 binding to its receptor CCR1 [31].

Regulatory relationships of CCL3

• Increase of CCR1 and CCR5 expression and enhanced functional response to MIP-1 alpha during differentiation of human monocytes to macrophages [32].
• In previous investigations, we have demonstrated that increased monocyte-derived MIP-1 alpha production was induced by intracellular adhesion molecule-1 (ICAM-1) interactions on activated HUVECs [33].
• Of note, both IL-4 and IFN-gamma markedly enhanced CCL3-induced endocytosis of immature DCs [34].
• Some chemokines such as MIP-1 alpha also inhibit hematopoietic progenitor cell proliferation [35].
• LPS- and IL-1 beta-induced MIP-1 alpha mRNA expression was reduced by 43 +/- 5% (P < 0.01) and 41 +/- 4% (NS) [36].

Other interactions of CCL3

• Despite its weaker eosinophil-activating properties, MIP-1 alpha was at least 10 times more potent on a molar basis than RANTES at inducing [Ca2+]i changes [37].
• Human MIP-1 alpha elicited no response in canine dermis, whereas monocyte chemoattractant protein 1 caused mild perivascular cuffing with monocytes [38].
• Chemokines displayed a selective effect among different T cell subsets; MIP-1 beta had more potent action on CD8+ T cells and tumor infiltrating lymphocytes (TIL), whereas RANTES and MIP-1 alpha targeted selectively CD4+ T cells [39].
• U83A-Npep acted only as antagonist, efficiently blocking binding of CCL3 to CCR1 or CCR5 on differentiated monocytic/macrophage leukemic cells [40].
• MCP3, MIP1 alpha, and Rantes were equally able to cross-attenuate the migratory response of YT4/293 cells to one another [29].

Analytical, diagnostic and therapeutic context of CCL3

• CC chemokine ligand (CCL)2, CCL3 and CCL4 levels were measured in the bronchoalveolar lavage fluid (BALF) of 18 nonsmoker control subjects and 17 patients affected by IPF [41].
• Reverse transcription-polymerase chain reaction (RT-PCR) analysis of EBV- and LPS-stimulated cultures revealed that EBV inhibited MIP-1 alpha production on the transcriptional level [13].
• Cell associated MIP-1alpha was visualised immunohistochemically, and cell associated MIP-1alpha as well as MIP-1alpha secreted into the SF was assayed by ELISA [42].
• Using flow cytometry and a biotinylated human MIP-1alpha/avidin fluorescein conjugate, the expression of MIP-1alpha receptors on CD34+ cells was assessed [43].
• Quantitative real-time PCR confirmed the transcriptional upregulation of representative inflammation-related genes (CCL2 and CCL3) encoding the chemokines monocyte chemoattractant protein-1 and macrophage inflammatory protein 1alpha [44].

References