Effects of monomethylfumarate on human granulocytes.
Monomethylfumarate (MMF) is the most active metabolite of the new antipsoriasis drug Fumaderm. Because granulocytes play an important role in the pathophysiology of psoriasis, the effects of this drug on the functional activities of these cells were investigated. MMF stimulated polarization and elastase release, and enhanced the intracellular killing of bacteria by granulocytes. This compound suppressed the formyl-Met-Nle-Phe (FMLP)-stimulated respiratory burst in these cells. MMF and dimethylfumarate but not its stereoisomer dimethylmaleate, fumaric acid, or dimethylmalate stimulated polarization of and elastase release by granulocytes, indicating that methylated fumarate derivatives interact with granulocytes in a specific fashion. MMF did not affect the binding of formyl-Nle-Leu-Phe-Nle-Tyr-Lys-fluorescein isothiocyanate to the FMLP receptor on granulocytes. This compound induced an increase in the intracellular Ca++ ([Ca++]i) and cyclic adenosine monophsphate concentration. The agonistic effects of MMF on granulocytes are thought to be mediated by the rise in the [Ca++]i and the antagonistic effects by the increase in the cyclic adenosine monophosphate concentration. These effects of MMF on granulocytes may in part explain the beneficial action of methylated fumarate derivatives on psoriatic skin lesions.
Nibbering
P H
PH
Department of Infectious Diseases, University Hospital, Leiden, The Netherlands.
Thio
B
B
Zomerdijk
T P
TP
Bezemer
A C
AC
Beijersbergen
R L
RL
van Furth
R
R
D001770:Blood Bactericidal Activity / Q000187:drug effects; D016764:Cell Polarity; D002474:Cell-Free System; D002634:Chemotaxis, Leukocyte; D000242:Cyclic AMP / Q000378:metabolism; D016650:Fluorescein-5-isothiocyanate; D005650:Fumarates / Q000494:pharmacology*; D006098:Granulocytes / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D006801:Humans; D008298:Maleates / Q000494:pharmacology*; D009161:Mycobacterium; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D009247:NADH, NADPH Oxidoreductases / Q000378:metabolism; D009842:Oligopeptides / Q000378:metabolism; D010101:Oxygen Consumption / Q000187:drug effects; D010196:Pancreatic Elastase / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D013268:Stimulation, Chemical
D005650:Fumarates; D008298:Maleates; D009842:Oligopeptides; D017382:Reactive Oxygen Species; C073341:citraconic acid; D009240:N-Formylmethionine Leucyl-Phenylalanine; C021642:F-chemotactic peptide; D000242:Cyclic AMP; D009247:NADH, NADPH Oxidoreductases; D010196:Pancreatic Elastase; D016650:Fluorescein-5-isothiocyanate