Prostaglandin E2 ( PGE2) is an important inducer of inflammation, which is also closely linked to the progress of tumours. In macrophages, PGE2 production is regulated by arachidonic acid release and cyclooxygenase-2 ( COX-2) expression. In the present study, we found that COX-2 expression can be achieved by activating Ca2+/ Calmodulin ( Ca M)-dependent protein kinase II ( Ca MKII) and c AMP-response element-binding protein ( CREB) in rat peritoneal macrophages. Our results indicated that lipopolysaccharide and PMA could elicit the transient increase of the concentration of intracellular free calcium ions ([ Ca2+]i), which induced activation of Ca MKs with the presence of Ca M. The subtype of Ca MKs, Ca MKII, then triggered the activation of CREB, which elevated COX-2 expression and PGE2 production in a chronological order. These results suggested that Ca2+/ Ca M-dependent Ca MKII plays an important role in mediating COX-2 expression and PGE2 production by activating CREB in macrophages. The study also provides more useful information to clarify the mechanism of calcium regulation of PGE2 production, which plays an essential role in inflammation and cancers. [ABSTRACT FROM AUTHOR]