EFFECTS OF MONOMETHYLFUMARATE ON HUMAN GRANULOCYTES

Monomethylfumarate (MMF) is the most active metabolite of the new anti psoriasis drug Fumaderm. Because granulocytes play an important role i n the pathophysiology of psoriasis, the effects of this drug on the fu nctional activities of these cells were investigated. MMF stimulated p olarization and elastase release, and enhanced the intracellular killi ng of bacteria by granulocytes. This compound suppressed the formyl-Me t-Nle-Phe (FMLP) - stimulated respiratory burst in these cells. MMF an d dimethylfumarate but not its stereo-isomer dimethylmaleate, fumaric acid, or dimethylmalate stimulated polarization of and elastase releas e by granulocytes, indicating that methylated fumarate derivatives int eract with granulocytes in a specific fashion. MMF did not affect the binding of formyl-Nle-Leu-Phe-Nle-Tyr-Lys-fluorescein isothiocyanate t o the FMLP receptor on granulocytes. This compound induced an increase in the intracellular Ca++ ([Ca++]i) and cyclic adenosine monophosphat e concentration. The agonistic effects of MMF on granulocytes are thou ght to be mediated by the rise in the [Ca++]i and the antagonistic eff ects by the increase in the cyclic adenosine monophosphate concentrati on. These effects of MMF on granulocytes may in part explain the benef icial action of methylated fumarate derivatives on psoriatic skin lesi ons.