CK beta 8/CCL23 induces cell migration via the G(i)/G(o) protein/PLC/PKC delta/NF-kappa B and is involved in inflammatory responses

Abstract

Aims: 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. Although it has been reported that CK beta 8 and CK beta 8-1 are implicated in leukocyte trafficking and development of inflammation, the exact roles of these two chemokines in immune responses and the associated chemotaxis signaling are still obscure. Main methods: To understand the mechanism of CK beta 8- and CK beta 8-1-induced chemotaxis signaling, we examined the chemotactic activities of osteogenic sarcoma cells expressing CC chemokine receptor I in response to CK beta 8 and CK beta 8-1. We also examined involvement of CK beta 8 and CK beta 8-1 in inflammatory responses by determining the mRNA expression of pro-inflammatory molecules induced by two chemokines and expressions of these chemokines in foam cells. Key findings: Results from a chemotaxis assay using various inhibitors for signaling molecules showed that the chemotaxis signal pathway induced by both CK beta 8 and CK beta 8-1 was mediated via the G(i)/G(o) protein, phospholipase C (PLC) and protein kinase C delta (PKC delta). Treatment with a nuclear factor kappa B (NF-kappa B) inhibitor reduced the chemotactic activities of CK beta 8 and CK beta 8-1, and NF-kappa B was activated in response to CK beta 8 and CK beta 8-1. In addition, CK beta 8 and CK beta 8-1 increased mRNA expression of pro-inflammatory cytokines and adhesion molecules. The mRNA levels of CK beta 8 and CK beta 8-1 were increased in foam cells. Significance: These results indicate that both CK beta 8 and CK beta 8-1 transduce the chemotaxis signal through the G(i)/G(o) protein, PLC, PKC delta, and NF-kappa B, and that CK beta 8 and CK beta 8-1 probably play important roles in inflammatory diseases such as atherosclerosis. (C) 2009 Elsevier Inc. All rights reserved.