Protein kinase C-dependent effects on leukocyte migration of thalidomide

Thalidomide is effective in the treatment of some tumor necrosis factor-rel ated diseases, but its cellular target is not known. Effects of thalidomide were investigated an lymphocytes and monocytes, Cell migration was examine d in a Boyden chamber. Effects on protein kinase C (PKC) were investigated functionally by use of PKC inhibitor and in purified enzyme preparations. T halidomide itself showed no direct chemotactic effect on lymphocytes or mon ocytes, Preincubation with the drug significantly enhanced random migration of both cell types. This effect was bisindolylmaleimide-reversible, sugges ting involvement of PKC, Preincubation with thalidomide diminished the chem otactic response of monocytes towards formyl peptide but failed to influenc e lymphocyte chemotaxis towards RANTES or interleukin-8. In a cell-free ass ay, inhibition of PKC activation by bisindolylmaleimide could be reversed b y thalidomide, indicating direct interactions of thalidomide with PKC. Resu lts suggest that effects of thalidomide in chronic inflammation may be rela ted to actions on leukocyte functions.