CKbeta8/CCL23 is a CC chemokine and alternative splicing of the CKbeta8 gene produces two mRNAs that encode CKbeta8 and its isoform CKbeta8-1. 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 CKbeta8 and CKbeta8-1 in cell proliferation, we examined the effects of CKbeta8 and CKbeta8-1 in the cell cycle. Both CKbeta8 and CKbeta8-1 induced cell-cycle progression. We next investigated whether MAPKs are involved in CKbeta8- and CKbeta8-1-induced cell proliferation. CKbeta8- and CKbeta8-1-stimulated cells showed phosphorylation of ERK1/2 and an inhibitor study indicated that CKbeta8- and CKbeta8-1-induced activation of ERK1/2 is mediated by the G(i)/G(o) protein, PLC, and PKCdelta. CKbeta8 and CKbeta8-1 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 CKbeta8 and CKbeta8-1 are involved in cell proliferation by modulating the cell cycle regulators.