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Effect of elevated cAMP on macrophage differentiation

Macrophages (Mφ) can be differentiated from monocytes (MO) through exposure to various cytokines, such as GM‐CSF and M‐CSF. Increased cAMP levels can have long‐lasting effects on the final phenotype of a differentiating MO, as well as more immediate effects on the inflammatory functions of activated Mφs. Previous studies using elevated cAMP have focused on the blunted inflammatory response of the treated Mφs to LPS challenge, but have not looked at the effects of cAMP on monocytic differentiation with GM‐CSF. We show here that MO to Mφ differentiation in the presence of elevated cAMP leads to a greatly altered final phenotype. This phenotype is currently being characterized using cDNA microarrays, real‐time PCR, FACS and ELISA techniques. Overall, Mφ differentiation is not affected, as indicated by no change in key surface Mφ markers. However, we see large fold increases in the message and protein levels of the CXCL family of chemokines, among other genes. Since the major cyclic nucleotide phosphodiesterase in these cells is PDE4A, a cAMP‐degrading PDE, these results are likely to have major ramifications for the use of PDE4 inhibitors as anti‐inflammatory agents.