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Mechanism of histamine release by formyl methionine-containing peptides
Abstract:
Small, acylated, methionine-containing peptides release histamine from human basophils. The characteristics of this reaction were compared to that of C5a- and IgE-induced release. fMet peptide-induced release requires Ca++ and is inhibited by EDTA in a manner similar to IgE- and C5a-mediated reactions. The fMet-Phe-Met-initiated reaction is complete within 2 min at temperatures of 25, 30, and 37 degrees C; but does not occur at 0 degrees C. There was a large variation in the capacity of leukocytes from different donors to release histamine with fMet peptides. However, there was no correlation in the capacity of leukocytes to release histamine with fMet-Phe-Met and their release with C5a or anti-IgE. The release by fMet-Phe-Met (but not by C5a or anti-IgE) was reversibly inhibited by a nonreleasing tripeptide. Leukocytes could be desensitized to the action of active fMet-peptide by preincubation with the peptide in the absence of cations. After washing, these cells released normally with C5a or anti-IgE. Conversely, cells desensitized to the action of C5a- or IgE-mediated reactions released normally with fMet peptides. There was cross-desensitization between different active peptides, and inactive peptides could not desensitize the leukocytes. Pharmacologic agents had similar effects on C5a and fMet peptide-induced release (e.g., lack of enhancement with deuterium oxide; enhancement with cytochalasin B; and inhibition with aminophylline and dibutyryl cyclic AMP). Therefore, histamine release with fMet peptides is initiated by their binding to and activation of a specific receptor on the basophil; the reaction beyond that point is similar to the C5a-mediated reaction.
Insights
Small, acylated, methionine-containing peptides trigger histamine release from human basophils. This process involves specific receptors and shares similarities with C5a- and IgE-mediated reactions.
Area of Science:
- Immunology
- Cell Biology
- Pharmacology
Background:
- Histamine release from basophils is a key inflammatory response.
- This release can be triggered by various stimuli, including complement component 5a (C5a) and immunoglobulin E (IgE).
- The role of small peptides in modulating this response is of significant interest.
Purpose of the Study:
- To characterize the histamine release induced by small, acylated, methionine-containing peptides (fMet peptides) from human basophils.
- To compare the mechanisms of fMet peptide-induced histamine release with those induced by C5a and IgE.
- To investigate the involvement of specific receptors and downstream signaling pathways.
Main Methods:
- Human basophils were isolated and incubated with fMet peptides, C5a, and anti-IgE.
- Histamine release was measured using various techniques, including cation dependency assays and temperature-dependent studies.
- Desensitization experiments and the effects of pharmacologic agents were evaluated.
Main Results:
- fMet peptide-induced histamine release requires calcium (Ca++) and is inhibited by EDTA, similar to C5a and IgE.
- The reaction is rapid, temperature-dependent, and shows significant inter-donor variability.
- Cross-desensitization was observed between different active peptides, but not between fMet peptides and C5a/IgE, suggesting distinct receptor interactions.
Conclusions:
- Histamine release by fMet peptides is initiated by binding to and activating specific receptors on basophils.
- The downstream signaling pathway for fMet peptide-induced release is largely conserved with C5a-mediated pathways.
- These findings elucidate a novel pathway for histamine release and its modulation in allergic and inflammatory conditions.