Interactions of calcium/calmodulin-dependent protein kinases (CaMK) and extracellular-regulated kinase (ERK) in monocyte adherence and TNF alpha production

The circulating monocyte possesses a markedly different functional phenotyp e relative to the macrophage (M phi). The adhesive interactions encountered by the monocyte, en route to the inflammatory focus, generate signals that culminate in the expression of a pro-inflammatory M phi phenotype, marked by enhanced cytokine production. Previously, we demonstrated that calcium a nd calmodulin are essential for maximal M phi activation and, in particular , TNF alpha production. These effects are likely to be mediated through sig nal transduction kinases that require the calcium/calmodulin complex. Here, we investigated the effect of adherence on calcium/calmodulin-dependent pr otein kinase (CaMK) II and IV activation of the extracellular-signal regula ted kinase (ERK) 1/2 cascade and on lipopolysaccharide (LPS)-induced TNF al pha production by human monocytes. Adherence activated ERK 1/2 and led to a n 8-fold potentiation in LPS-induced TNF alpha production over similarly st imulated non-adherent cells. Inhibition of CaMK II prior to adherence preve nted ERK 1/2 activation and attenuated by up to 40%, the TNF alpha response to subsequent LPS stimulation. CaMK II inhibition after adherence, however , failed to modify cytokine release. Inhibition of CaMK IV, both after adhe rence and in non-adherent monocytes, significantly inhibited LPS-induced ER K 1/2 activation and abrogated TNF alpha production by up to 75%. These dat a suggest that the function of CaMK II in TNF alpha production by adherent monocytes occurs during adhesion, is mediated in part by activation of ERK 1/2, and appears to "prime" the monocyte for enhanced cytokine production. CaMK IV, through activation of ERK 1/2, appears to have a direct role in th e LPS signal transduction for TNF alpha production.