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Leukotriene B4 mediates substance P-induced granulocyte infiltration into mouse skin. Comparison with antigen-induced
I Iwamoto1, S Tomoe, H Tomioka
1Second Department of Internal Medicine, Chiba University School of Medicine, Japan.
Abstract:
Substance P, a potent proinflammatory peptide present in sensory neurons, causes granulocyte (neutrophil and eosinophil) infiltration into mouse skin by inducing mast cell degranulation. However, the mediator responsible for this granulocyte infiltration has not been determined. In this study, we determined which mediator from cutaneous mast cells mediates substance P-induced granulocyte infiltration in the skin by the use of two mediator antagonists; one for platelet activating factor (PAF) CV-6209 and the other for leukotriene B4 (LTB4) ONO-4057. Subcutaneous injection of substance P (10(-7)-10(-5) M) caused granulocyte infiltration in the skin of BALB/c mice in a time- and concentration-dependent fashion. Pretreatment with the LTB4 antagonist decreased substance P-induced neutrophil and eosinophil infiltration into mouse skin at 6 h to the same extent that an inhibitor of mast cell degranulation, disodium cromoglycate, decreased those responses. However, pretreatment with the PAF antagonist affected neither substance P-induced neutrophil nor eosinophil infiltration at 6 h. A LTC4/D4 antagonist ONO-1078 and a histamine H1 antagonist chlorpheniramine had no effect on the granulocyte infiltration, either. The LTB4 antagonist also decreased substance P-induced neutrophil, but not eosinophil, infiltration into mouse skin at 24 h. In contrast, the PAF antagonist inhibited Ag-induced eosinophil infiltration of mouse skin, whereas the LTB4 antagonist inhibited the Ag-induced neutrophil infiltration. We conclude that LTB4 is a major mast cell-derived chemotactic mediator for initiating substance P-induced neutrophil and eosinophil infiltration into mouse skin. Our results suggest that LTB4 antagonists might be useful in preventing such neurogenic inflammation.
Insights
Leukotriene B4 (LTB4) is identified as the primary mediator from mast cells that drives granulocyte infiltration in response to Substance P in mouse skin, suggesting LTB4 antagonists for neurogenic inflammation treatment.
Area of Science:
- Immunology
- Dermatology
- Neuroscience
Background:
- Substance P, a neuropeptide, triggers mast cell degranulation and subsequent granulocyte infiltration in the skin.
- The specific mast cell mediator responsible for Substance P-induced granulocyte infiltration remains unidentified.
Purpose of the Study:
- To identify the key mediator released by cutaneous mast cells that mediates granulocyte infiltration induced by Substance P.
- To evaluate the roles of platelet-activating factor (PAF) and leukotriene B4 (LTB4) in this process.
Main Methods:
- Subcutaneous injection of Substance P in BALB/c mice.
- Administration of specific antagonists for LTB4 (ONO-4057) and PAF (CV-6209) prior to Substance P.
- Assessment of granulocyte (neutrophil and eosinophil) infiltration at 6 and 24 hours.
- Comparison with disodium cromoglycate (mast cell stabilizer) and other antagonists (ONO-1078, chlorpheniramine).
Main Results:
- LTB4 antagonist significantly reduced Substance P-induced neutrophil and eosinophil infiltration at 6 hours, comparable to disodium cromoglycate.
- PAF antagonist showed no significant effect on Substance P-induced infiltration at 6 hours.
- LTB4 antagonist reduced neutrophil infiltration at 24 hours, while PAF antagonist inhibited antigen-induced eosinophil infiltration.
Conclusions:
- Leukotriene B4 (LTB4) is a major mast cell-derived chemotactic mediator responsible for initiating Substance P-induced neutrophil and eosinophil infiltration in mouse skin.
- LTB4 antagonists may hold therapeutic potential for preventing neurogenic inflammation characterized by granulocyte infiltration.