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Effects of monomethylfumarate on human granulocytes
P H Nibbering1, B Thio, T P Zomerdijk
1Department of Infectious Diseases, University Hospital, Leiden, The Netherlands.
Abstract:
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.
Insights
Monomethylfumarate (MMF), a metabolite of Fumaderm, enhances granulocyte functions crucial for fighting psoriasis. It boosts bacterial killing and elastase release while suppressing respiratory bursts, potentially explaining its therapeutic benefits.
Area of Science:
- Immunology
- Dermatology
- Pharmacology
Background:
- Psoriasis pathophysiology involves granulocytes.
- Fumaderm is a new antipsoriasis drug with Monomethylfumarate (MMF) as its active metabolite.
Purpose of the Study:
- Investigate the effects of MMF on granulocyte functional activities.
- Determine the mechanisms behind MMF's action on granulocytes.
Main Methods:
- Assessed granulocyte polarization, elastase release, and intracellular bacterial killing.
- Measured FMLP-stimulated respiratory burst and FMLP receptor binding.
- Monitored intracellular calcium ([Ca++]i) and cyclic adenosine monophosphate (cAMP) concentrations.
Main Results:
- MMF stimulated granulocyte polarization, elastase release, and bacterial killing.
- MMF suppressed FMLP-stimulated respiratory burst without affecting FMLP receptor binding.
- MMF increased intracellular [Ca++]i and cAMP levels.
Conclusions:
- MMF exhibits specific interactions with granulocytes, modulating their functional activities.
- Increased [Ca++]i may mediate MMF's agonistic effects, while increased cAMP may mediate its antagonistic effects.
- These granulocyte-modulating effects of MMF may contribute to its efficacy in treating psoriatic lesions.