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 phenotype 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 and calmodulin are essential for maximal M phi activation and, in particular, TNF alpha production. These effects are likely to be mediated through signal transduction kinases that require the calcium/calmodulin complex. Here, we investigated the effect of adherence on calcium/calmodulin-dependent protein kinase (CaMK) II and IV activation of the extracellular-signal regulated kinase (ERK) 1/2 cascade and on lipopolysaccharide (LPS)-induced TNF alpha production by human monocytes. Adherence activated ERK 1/2 and led to an 8-fold potentiation in LPS-induced TNF alpha production over similarly stimulated non-adherent cells. Inhibition of CaMK II prior to adherence prevented 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 adherence and in non-adherent monocytes, significantly inhibited LPS-induced ERK 1/2 activation and abrogated TNF alpha production by up to 75%. These data 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 the LPS signal transduction for TNF alpha production.