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

CK beta 8/CCL23 is a CC chemokine and alternative splicing of the CK beta 8 gene produces two mRNAs that encode CK beta 8 and its isoform CK beta 8-1. 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 CK beta 8 and CK beta 8-1 in cell proliferation, we examined the effects of CK beta 8 and CK beta 8-1 in the cell cycle. Both CK beta 8 and CK beta 8-1 induced cell-cycle progression. We next investigated whether MAPKs are involved in CK beta 8- and CK beta 8-1-induced cell proliferation. CK beta 8- and CK beta 8-1-stimulated cells showed phosphorylation of ERK1/2 and an inhibitor study indicated that CK beta 8- and CK beta 8-1-induced activation of ERK1/2 is mediated by the G(i)/G(o) protein, PLC, and PKC delta. CK beta 8 and CK beta 8-1 regulated expression of the cell cycle regulators cyclin D-3 and cyclin B-1, and the immediate early response gene products c-Myc and Egr-1. These results indicate that both CK beta 8 and CK beta 8-1 are involved in cell proliferation by modulating the cell cycle regulators. (C) 2009 Elsevier Ltd. All rights reserved.