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Oxidative priming of neutrophils by interferon-gamma
S D Tennenberg1, D E Fey, M J Lieser
1Department of Surgery, Wayne State University School of Medicine, Allen Park Veterans Affairs Medical Center, Detroit, Michigan 48101.
Abstract:
Priming of neutrophil (PMN) oxidative responses is an integral component of host defense and inflammation and may contribute to cell-mediated tissue injury. The characteristics and mechanisms of interferon-gamma (IFN-gamma)-induced oxidative priming of PMNs were explored in vitro. Following pretreatment of human PMNs with recombinant IFN-gamma, superoxide anion release was selectively primed toward the receptor-initiated stimulants f-Met-Leu-Phe (fMLP) and C5a but not toward the transduction-mediated stimulants phorbol myristate acetate and A23187, a calcium ionophore. IFN-gamma also induced priming toward the stimulant NaF, a direct activator of guanine nucleotide regulatory proteins. Priming was not associated with changes in fMLP surface receptor expression or degranulation. Priming was dependent on de novo mRNA and protein synthesis. The immuno-regulatory lymphokine IFN-gamma primes PMN oxidative responses, apparently via production of proteins that are involved in the early postreceptor transductional pathways of oxidative metabolism.
Insights
Interferon-gamma (IFN-gamma) selectively primes neutrophil superoxide anion release in response to specific stimuli. This priming requires new protein synthesis and impacts early signaling pathways in host defense.
Area of Science:
- Immunology
- Cell Biology
- Biochemistry
Background:
- Neutrophil (PMN) oxidative responses are crucial for host defense and inflammation.
- Dysregulated oxidative responses can contribute to tissue injury.
Purpose of the Study:
- To investigate the mechanisms of interferon-gamma (IFN-gamma)-induced oxidative priming of human neutrophils (PMNs) in vitro.
- To determine the signaling pathways affected by IFN-gamma priming.
Main Methods:
- Human PMNs were pretreated with recombinant IFN-gamma.
- Superoxide anion release was measured in response to various stimuli, including f-Met-Leu-Phe (fMLP), C5a, phorbol myristate acetate, A23187, and NaF.
- fMLP surface receptor expression and degranulation were assessed.
- The role of de novo mRNA and protein synthesis was evaluated.
Main Results:
- IFN-gamma selectively primed superoxide anion release towards receptor-initiated (fMLP, C5a) and guanine nucleotide regulatory protein-activating (NaF) stimuli, but not transduction-mediated stimuli (phorbol myristate acetate, A23187).
- Priming did not alter fMLP receptor expression or degranulation.
- Priming was dependent on de novo mRNA and protein synthesis.
Conclusions:
- The immuno-regulatory lymphokine IFN-gamma primes PMN oxidative responses.
- This priming appears to involve the production of proteins that modulate early post-receptor signal transduction pathways in oxidative metabolism.