Adenosine inhibits platelet-activating factor, but not tumour necrosis factor-alpha-induced priming of human
1Department of Physiology, University of Melbourne, Parkville, Victoria, Australia.
Abstract:
Regulation of the respiratory burst and its priming by recombinant human tumour necrosis factor-alpha (rhTNF-alpha) and platelet-activating factor (PAF) were investigated in human polymorphonuclear leucocytes (PMN). Adenosine (0.1-10 microM) pretreatment of PMN concentration-dependently inhibited the superoxide anion generation (O2-) in response to formyl-methionyl-leucyl-phenylalanine (FMLP). The priming by PAF (1 microM) for an increased O2- generation by FMLP-stimulated PMN was completely blocked by adenosine pretreatment. In contrast, rhTNF-alpha-induced priming was unaffected by adenosine. In addition, the direct stimulation of PMN O2- by rhTNF-alpha was also unaffected by adenosine as was rhTNF-alpha-induced PAF synthesis. FMLP-induced PAF synthesis was reduced by adenosine to a similar extent as the inhibition of the respiratory burst. Adenosine also inhibited PAF-, but not FMLP-induced increases in intracellular calcium in PMN. These findings indicate that short-term, direct stimulants (FMLP) or priming agents (PAF) are subject to modulation by the endothelial product adenosine, whereas the priming and direct stimulation of the respiratory burst by the longer-acting agent, rhTNF-alpha is unaffected. Moreover, differential inhibition of PMN activation by adenosine reveals important functional differences in the signalling mechanisms initiated by PAF, FMLP and rhTNF-alpha.
Insights
Adenosine inhibits superoxide generation in human polymorphonuclear leucocytes (PMN) stimulated by FMLP and PAF, but not by TNF-alpha. This highlights distinct signaling pathways for PMN activation by different agents.
Area of Science:
- Immunology
- Cellular Biology
- Pharmacology
Background:
- The respiratory burst in human polymorphonuclear leucocytes (PMN) is crucial for pathogen clearance.
- Tumor necrosis factor-alpha (TNF-alpha) and platelet-activating factor (PAF) are key modulators of PMN activation.
- Adenosine, an endogenous nucleoside, plays a role in regulating inflammatory responses.
Purpose of the Study:
- To investigate the regulatory effects of adenosine on the respiratory burst and priming in human PMN.
- To compare the influence of adenosine on PMN activation induced by formyl-methionyl-leucyl-phenylalanine (FMLP), PAF, and recombinant human TNF-alpha (rhTNF-alpha).
Main Methods:
- Human PMN were pretreated with varying concentrations of adenosine.
- Superoxide anion (O2-) generation was measured in response to FMLP, PAF, and rhTNF-alpha stimulation.
- Intracellular calcium levels were monitored following stimulation with PAF and FMLP.
- PAF synthesis was assessed in response to FMLP and rhTNF-alpha.
Main Results:
- Adenosine inhibited FMLP-induced O2- generation in a concentration-dependent manner.
- Adenosine completely blocked PAF-induced priming of PMN for enhanced O2- generation by FMLP.
- Adenosine did not affect rhTNF-alpha-induced priming or direct O2- stimulation.
- Adenosine reduced FMLP-induced PAF synthesis and inhibited PAF-induced calcium increases, but not FMLP-induced calcium increases.
Conclusions:
- Adenosine differentially modulates PMN activation, inhibiting responses to FMLP and PAF but not rhTNF-alpha.
- These findings suggest distinct intracellular signaling mechanisms for PMN activation by FMLP, PAF, and rhTNF-alpha.
- Adenosine's selective inhibition highlights its potential as a regulator of inflammatory processes involving PMN.
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