CKβ8/CCL23 and its isoform CKβ8-1 induce up-regulation of cyclins via the G_i/G_o protein/PLC/PKCδ/ERK leading to cell-cycle progression

CKβ8/CCL23 is a CC chemokine and alternative splicing of the CKβ8 gene produces two mRNAs that encode CKβ8 and its isoform CKβ8-1. Chemokines play a critical role in leukocyte trafficking and development of inflammation and chemokines are also known to be involved in cell proliferation. To investigate participation of CKβ8 and CKβ8-1 in cell proliferation, we examined the effects of CKβ8 and CKβ8-1 in the cell cycle. Both CKβ8 and CKβ8-1 induced cell-cycle progression. We next investigated whether MAPKs are involved in CKβ8- and CKβ8-1-induced cell proliferation. CKβ8- and CKβ8-1-stimulated cells showed phosphorylation of ERK1/2 and an inhibitor study indicated that CKβ8- and CKβ8-1-induced activation of ERK1/2 is mediated by the G_i/G_o protein, PLC, and PKCδ. CKβ8 and CKβ8-1 regulated expression of the cell cycle regulators cyclin D₃ and cyclin B_1, and the immediate early response gene products c-Myc and Egr-1. These results indicate that both CKβ8 and CKβ8-1 are involved in cell proliferation by modulating the cell cycle regulators.