Protein kinase C-dependent effects on leukocyte migration of thalidomide

Abstract

Thalidomide is effective in the treatment of some tumor necrosis factor- related diseases, but its cellular target is not known. Effects of thalidomide were investigated on lymphocytes and monocytes. Cell migration was examined in a Boyden chamber. Effects on protein kinase C (PKC) were investigated functionally by use of PKC inhibitor and in purified enzyme preparations. Thalidomide itself showed no direct chemotactic effect on lymphocytes or monocytes. Preincubation with the drug significantly enhanced random migration of both cell types. This effect was bisindolylmaleimide- reversible, suggesting involvement of PKC. Preincubation with thalidomide diminished the chemotactic response of monocytes towards formyl peptide but failed to influence lymphocyte chemotaxis towards RANTES or interleukin-8. In a cell-free assay, inhibition of PKC activation by bisindolylmaleimide could be reversed by thalidomide, indicating direct interactions of thalidomide with PKC. Results suggest that effects of thalidomide in chronic inflammation may be related to actions on leukocyte functions.