beta-chemokine induction of activation protein-1 and cyclic AMP responsiveelement activation in human myeloid cells

Chemokines effect leukocyte chemotaxis and activation through their binding to specific G protein-coupled receptors. Although early steps in chemokine signal transduction pathways have been characterized, there is relatively limited information available at the transcription factor level. To that en d, we have examined the binding activity on activation protein-1 (AP-1) and cyclic AMP responsive element (CRE) target sequences in human THP-1 myeloi d cells after treatment with the beta -chemokine macrophage inflammatory pr otein (MIP-1 alpha). MIP-1 alpha induced both AP-1 and CRE activation. Alth ough inhibition of protein kinase C blocked the AP-1 activity induced by th is chemokine, there was no decrease in CRE activation in the presence of a protein kinase A inhibitor. Using kinase assays, it appeared that mitogen-a ctivated protein kinase pathways were involved in CRE activation. In additi on, HIV-1 infection of THP-1 cells resulted in constitutive activation of A P-1 and CRE elements but no further response to MIP-1 alpha treatment. Thes e results suggest that beta -chemokines act via protein kinase C-dependent pathways and mitogen-activated protein kinase pathways to modulate the host transcriptional response in myeloid cells, and that this response is alter ed by HIV infection.