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Acidic polyamino acids inhibit human eosinophil granule major basic protein toxicity. Evidence of a functional role
R L Barker1, R H Gundel, G J Gleich
1Department of Immunology, Mayo Clinic School, Rochester, Minnesota 55905.
Abstract:
Eosinophil granule major basic protein (MBP), a potent toxin for helminths and mammalian cells in vitro, is a single polypeptide chain rich in arginine. MBP has been localized on damaged helminths and tissues in hypersensitivity diseases including bronchial asthma. The MBP cDNA indicates that MBP is translated as a slightly acidic preproprotein with an acidic propart. To test the hypothesis that the acidic pro-part of proMBP inhibits the toxicity of mature MBP, acidic polyamino acids (aa) were used as antagonists of MBP toxicity to K562 cells and guinea pig tracheal epithelium and used as antagonists of MBP airway hyperresponsiveness in primates. The acidic poly aa inhibited MBP toxicity and MBP airway hyperresposiveness. The acidic poly aa inhibited MBP toxicity in a charge-dependent manner similar to that proposed for proMBP, suggesting that the acidic pro-part of proMBP functions to mask mature MBP toxicity. This inhibition was not limited to MBP, but also applied to polyarginine and eosinophil cationic protein. These acidic poly aa may be useful to inhibit the actions of a number of cationic toxins released by the eosinophil in numerous hypersensitivity diseases.
Insights
The acidic pro-part of eosinophil major basic protein (MBP) inhibits its toxicity. Acidic polyamino acids mimicked this inhibition, suggesting a potential therapeutic strategy for hypersensitivity diseases.
Area of Science:
- Immunology
- Cell Biology
- Biochemistry
Background:
- Eosinophil granule major basic protein (MBP) is a potent arginine-rich toxin implicated in helminth damage and hypersensitivity diseases like asthma.
- MBP is synthesized as a precursor (proMBP) with an acidic pro-part, whose function in modulating MBP toxicity is unclear.
Purpose of the Study:
- To test the hypothesis that the acidic pro-part of proMBP inhibits the toxicity of mature MBP.
- To investigate the potential therapeutic application of acidic polyamino acids in counteracting eosinophil-derived cationic toxins.
Main Methods:
- Acidic polyamino acids were employed as antagonists to assess their effect on MBP toxicity to K562 cells and guinea pig tracheal epithelium.
- The impact of acidic polyamino acids on MBP-induced airway hyperresponsiveness in primates was evaluated.
- Charge-dependent inhibition patterns were analyzed.
Main Results:
- Acidic polyamino acids effectively inhibited MBP toxicity and airway hyperresponsiveness in a charge-dependent manner.
- The inhibitory mechanism mirrored the proposed function of the proMBP's acidic pro-part in masking MBP toxicity.
- Inhibition extended to other cationic eosinophil proteins like polyarginine and eosinophil cationic protein.
Conclusions:
- The acidic pro-part of proMBP likely serves to inhibit the potent toxicity of mature MBP.
- Acidic polyamino acids demonstrate potential as therapeutic agents to neutralize various cationic toxins released by eosinophils in hypersensitivity conditions.
