Disease relevance of CCL3L1

• Strong interaction with CCR5 means that CCL3-L1, and particularly its -2 variant, are by far the most potent natural HIV entry inhibitors described to date [1].
• These findings, derived from the largest genetic study of any systemic vasculitis, suggest a central role of CCR5-CCL3L1 gene-gene interactions in KD susceptibility and the importance of gene modifiers in infectious diseases [2].
• Genetic variations in the receptor-ligand pair CCR5 and CCL3L1 are important determinants of susceptibility to Kawasaki disease [2].
• In a recent study, a significant interindividual and interpopulation difference in the copy number of a segmental duplication encompassing the gene encoding CCL3L1, a potent human immunodeficiency virus-1 (HIV- 1)-suppressive chemokine was found [3].
• Possession of a CCL3L1 copy number lower than the population average was associated with markedly enhanced HIV/acquired immunodeficiency syndrome (AIDS) susceptibility [3].
• This study confirms a crucial protective role of CCL3L1 from both HIV infection and disease progression, highlighting a previously not described functional up-regulation of this chemokine variant in both HIV-positive and -negative persons infected with HTLV-2 [4].
• Lower CCL3L1 gene copy number compared to the population median is associated with chronic hepatitis C [5].

High impact information on CCL3L1

• Specific haplotypes encompassing the CCR5 and CCR2 loci, and the copy number of the CCL3L1 gene, have also been convincingly correlated with delayed progression [6].
• Analysis of the CCL3-L1 gene for association with HIV-1 susceptibility and disease progression [7].
• Sequences homologous to uCOM are found in the promoters of other inducible genes, coding for proteases, cytokines and chemokines: for example, in the promoter of the MIP-1alpha/LD78 chemokine gene, a 15/18 nucleotides identity is found in a region mediating positive and negative functions in TPA induction [8].
• Furthermore, AMD3451 inhibited CXCL12- and CCL3L1-induced endocytosis in CXCR4- and CCR5-transfected cells [9].
• However, the magnitude of the reduced risk of KD associated with the CCR5- Delta 32 allele and certain CCR5 haplotypes was significantly greater in individuals who also possessed a high copy number of the gene encoding CCL3L1, the most potent CCR5 ligand [2].

Biological context of CCL3L1

• These observations support the idea that the multiple copies of CCL3L1 and CCL4L1 present in a single diploid genome are the result of segmental duplication [10].
• CCL3L1 and CCL4L1 chemokine genes are located in a segmental duplication at chromosome 17q12 [10].
• As a result of these studies, we hypothesize that genetic variation in CCL3-L1 gene copy number may affect the susceptibility to, or the progression or severity of, diseases in which this chemokine plays a role [1].
• Four isoforms of the chemokine CCL3 with different amino termini (CCL3, CCL3(2-70), CCL3(5-70), CCL3L1) were tested in these assays in order to probe structure/activity relationships [11].
• Transfection of CCL3L1-expression vector to glioblastoma cell line enhanced proliferation of the tumor cells [12].

Anatomical context of CCL3L1

• Migration of Th1/CCR5+ and Th2/CCR4+ effector lymphocytes toward CCR5 (CCL5, CCL3L1) and CCR4 (CCL22) ligands is affected by cleavage [13].
• T-cell chemotactic activity of cytokine LD78: a comparative study with interleukin-8, a chemotactic factor for the T-cell CD45RA+ phenotype [14].
• The conditioned medium of KMT-2 cells or peripheral blood mononuclear cells cultured with LD78 suppressed colony formation by CD34+ cells [15].
• We performed a study of 25 AML patients at diagnosis to evaluate the effect of a human homolog of MIP-1 alpha (LD78) on bone marrow (BM) and peripheral blood (PB) leukemic progenitors (colony-forming unit-AML [CFU-AML]) and AML cell proliferation [16].
• The addition of doses of 100 ng/ml or more of LD78 suppressed the colony formation of KMT-2, a factor-dependent myelomonocytic cell line established from cord blood cells; this suppressive activity was neutralized by the addition of antibody against LD78 [15].

Associations of CCL3L1 with chemical compounds

• A proline at position 2 (CCL3L1) provides for high potency and efficacy but the isoform with a serine at position 2 (CCL3(2-70)) is as efficacious in some assays showing that the proline is not the only determinant of high efficacy [11].

Other interactions of CCL3L1

• Here, using real-time PCR we have shown that CCL3-L1 and a novel CCL4 isoform (termed CCL4-L1) can vary from 1-6 copies per diploid genome (pdg) in Caucasians and are occasionally completely absent [1].
• We suggest that the CUS-G0S19-3 sequence was generated by recombination between a G0S19-2 gene and a member of a novel CUS-associated gene family [17].
• Furthermore, it was confirmed that HM145 is a functional receptor for LD78, one of the C-C chemokines, as revealed by the measurement of decrease of cAMP accumulation as well as calcium influx using stable transfectants [18].
• These data suggest that increased expression of the CCL3L1, CCR3 and CCR5 chemokine-receptors system is involved in brain tumorigenesis, especially in the progression of glioblastoma [12].
• The same doses of LD78 suppressed the formation of neutrophil, macrophage, and megakaryocytic colonies which were supported by human interleukin-3 and erythropoietin; however, LD78 did not affect colony formation by either non-phagocytic mononuclear cells or sorted CD34+ cells [15].

Analytical, diagnostic and therapeutic context of CCL3L1

• Restriction mapping and sequencing shows a CpG-US-like sequence approximately 8 kb downstream of G0S19-2 (hence, named CpG-DS sequence) [19].

References