Disease relevance of CCL15

• Neutrophils were found to release CCL15 proteolytic activity in the course of hemofiltration of blood from renal insufficiency patients [1].
• To understand the mechanism of Lkn-1-induced chemotaxis signaling, we examined the chemotactic activities of human osteogenic sarcoma cells expressing CCR1 in response to Lkn-1 using inhibitors of signaling molecules [2].
• The ascites fluid contained the chemokines CCL10, CCL15, and CCL18 which was associated with a large influx of activated T cells, including CD8(+) T cells recognizing HLA-A2 tetramer complexes with peptides from Melan-A and NA17-A [3].
• Pertussis toxin, an inhibitor of G(i)/G(o) protein, and phospholipase C (PLC) inhibitor blocked Lkn-1-induced activation of ERK [4].
• These results raise the possibility that LKN-1 is another chemokine that is involved in the atherogenesis [5].

High impact information on CCL15

• Desensitization studies indicate that HCC-2 acts mainly via CC chemokine receptor CCR1 [6].
• HCC-2, a human chemokine: gene structure, expression pattern, and biological activity [6].
• In contrast to HCC-1, which is expressed constitutively in numerous human tissues, HCC-2 is expressed only in the gut and the liver [6].
• Highly purified recombinant HCC-2 was tested on neutrophils, eosinophils, monocytes, and lymphocytes and was found to exhibit marked functional similarities to macrophage inflammatory protein 1alpha [6].
• At variance with the genes for HCC-1 and other human CC chemokines, which have a three-exon-two-intron structure, the HCC-2 gene consists of four exons and three introns [6].

Biological context of CCL15

• Leukotactin-1/CCL15-induced chemotaxis signaling through CCR1 in HOS cells [2].
• In consensus with observations in the first scan, the present study identified haplotypes within CCL3 and CCL15 in the telomeric CCL cluster [7].
• When the nucleotide sequences of the MPIF-1 and HCC-2 genes are compared, they are well conserved, including introns and flanking sequences, except for the middle region of the long first intron, indicating that they have been generated recently in evolutionary terms by duplication [8].
• In contrast to most other human CC chemokine genes that consist of three exons, the MPIF-1 and HCC-2 genes, separated by 12 kb, have four exons [8].
• Involvement of two NF-kappaB binding sites in PMA-induced expression of the human leukotactin-1/CCL15 gene in U937 monocytoid cells [9].

Anatomical context of CCL15

• These proteins termed CCL3 (MIP-1alpha), CCL4 (MIP-1beta), CCL9/10 (MIP-1delta), and CCL15 (MIP-1gamma) according to the revised nomenclature for chemokines are produced by many cells, particularly macrophages, dendritic cells, and lymphocytes [10].
• Because a number of chemokines induce angiogenesis and endothelial cells express CCR1 and CCR3, we investigated the angiogenic activity of CCL15 [11].
• Compared with full-length CCL15, delta23 and delta26 isoforms displayed a significantly increased potency to induce calcium fluxes and chemotactic activity on monocytes and to induce adhesiveness of mononuclear cells to fibronectin [1].
• MIP-5 induces chemotaxis of human monocytes, T-lymphocytes and, to a lesser degree, eosinophils at nanomolar concentrations; it has no effect on neutrophil migration [12].
• Northern blot analysis and reverse-transcriptase PCR show that the mRNA for MIP-5 is expressed at a high levels in liver, intestine and in lung leukocytes [12].

Associations of CCL15 with chemical compounds

• Further we demonstrate that the third disulfide bond of CCL15 and an exchange of tyrosine in position 70 by a leucine residue, which is conserved in CXC chemokines, do not alter the interaction with CCR1 [13].
• Chemotactic activity of Lkn-1 was inhibited by the treatment of cycloheximide and actinomycin D suggesting that newly synthesized proteins are needed for chemotaxis [2].
• Deletion of 29 amino acids, however, abolished the agonistic activity almost completely showing that at least 3 amino acid residues preceding the first cysteine at the NH(2) terminus are essential for the biological activity of Lkn-1 [14].
• Serial deletion studies showed that at least three amino acid residues, alanine-alanine-aspartic acid (A-A-D), preceding the first cysteine at the NH(2)-terminus are essential for the biological activity of Lkn-1 [15].
• Protein kinase C delta (PKC delta) specific inhibitor rottlerin inhibited ERK activation in Lkn-1-stimulated cells [4].

Physical interactions of CCL15

• These data indicate that LZIP binds to CCR1 and that the interaction between CCR1 and LZIP participates in regulation of Lkn-1-dependent cell migration without affecting the chemotactic activities of other CC chemokines that bind to CCR1 [16].

Regulatory relationships of CCL15

• Our findings indicate that transcription of the CCL15 gene is regulated by AP-1 and NF-kappaB through MEK and JNK MAPK pathways in monocytoid cells [17].

Other interactions of CCL15

• Hemofiltrate CC chemokines with unique biochemical properties: HCC-1/CCL14a and HCC-2/CCL15 [18].
• In contrast, a CCL15 derivative lacking the carboxy-terminal alpha-helix exhibits a complete loss of tertiary structure and hence loss of CCR1 agonistic and binding activity [13].
• The present study replicates our previous findings and further suggests the existence of MS associated haplotypes within genes of CCL3 and CCL15 [7].
• We show here that neutrophils may support this process by activation of CCL15, a human chemokine circulating in blood plasma [1].
• Neutrophil cathepsin G was identified as the principal protease to produce delta23 and delta26 CCL15 [1].

Analytical, diagnostic and therapeutic context of CCL15

• Transcripts were not detected in the original HCC 1 and HCC2 upon Northern blot analysis [19].
• The expression level of Lkn-1 or its receptors mRNA was measured by RT-PCR analysis [20].
• Levels of plasma Lkn-1, MCP-1, ICAM-1 and total cholesterol were measured by ELISA or enzymatic assay [20].
• METHODS: From 1985 to 1994, 125 patients with solitary HCC 2 cm or less in greatest diameter underwent curative hepatectomy (liver segmentectomy or larger resection, 94; subsegmentectomy, 31) [21].

References