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Effect of substance P on superoxide anion and IL-8 production by human PMNL
M C Serra1, F Calzetti, M Ceska
1Institute of General Pathology, University of Verona, Italy.
Abstract:
The neuropeptide substance P (SP), a main mediator of neurogenic inflammation, has been shown to have direct and modulatory effects on functional responses of polymorphonuclear leucocytes (PMNL). In this study, we further investigated the effects exerted by SP on human PMNL functions. Pretreatment of PMNL with SP resulted in an increase of superoxide anion (O2-) production in response to formyl-methionyl-leucyl-phenylalanine (FMLP), concanavalin A (Con A) and opsonized zymosan (STZ). In contrast, the O2- production induced by tumour necrosis factor (TNF) was strongly inhibited by pretreatment with SP. Both enhancement and inhibition of O2- response were exerted by SP in a dose-dependent manner and at concentrations which did not directly stimulate O2- production. These effects were rapid in onset, and occurred after 5 min of preincubation of cells with the neuropeptide. At concentrations that modulated O2- production by PMNL, SP also directly stimulated release of the chemotactic cytokine interleukin-8 (IL-8). Induction of IL-8 release required a longer incubation time (1 hr) with SP and was preceded by an increase of IL-8 mRNA steady-state levels. Furthermore, as well as directly stimulating IL-8 production, SP was also able to enhance the IL-8 release induced by other stimuli such as FMLP and TNF. The results of this study indicate that, in addition to the rapid and differential modulation of O2- production, SP also induces long-term changes such as IL-8 synthesis and release, and can thus amplify the process of PMNL recruitment to the inflammatory site.
Insights
Substance P (SP) rapidly modulates human polymorphonuclear leucocyte (PMNL) functions, differentially affecting superoxide anion production and stimulating interleukin-8 (IL-8) release, crucial for inflammation.
Area of Science:
- Immunology
- Neuroscience
- Inflammation Research
Background:
- Substance P (SP) is a neuropeptide involved in neurogenic inflammation.
- SP influences the functional responses of polymorphonuclear leucocytes (PMNL).
Purpose of the Study:
- To investigate the specific effects of SP on human PMNL functions.
- To elucidate the mechanisms and timelines of SP-mediated PMNL modulation.
Main Methods:
- Human PMNL were pretreated with varying concentrations of SP.
- Superoxide anion (O2-) production was measured in response to stimuli like FMLP, Con A, STZ, and TNF.
- Interleukin-8 (IL-8) release and mRNA levels were assessed after SP incubation.
Main Results:
- SP enhanced O2- production stimulated by FMLP, Con A, and STZ, but inhibited TNF-induced O2- production.
- These modulatory effects were dose-dependent, rapid (onset within 5 min), and did not directly stimulate O2- production.
- SP induced IL-8 release and increased IL-8 mRNA levels after 1 hour, and also enhanced FMLP- and TNF-induced IL-8 release.
Conclusions:
- SP exerts rapid, differential effects on PMNL superoxide production.
- SP also induces longer-term changes in PMNL, including IL-8 synthesis and release.
- SP amplifies PMNL recruitment to inflammatory sites by modulating both O2- production and IL-8 release.