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Glucagon modulates superoxide generation in human polymorphonuclear leucocytes
L Al-essa1, M Niwa, M Kobayashi
1Department of Pharmacology, Gifu University School of Medicine, Japan.
Abstract:
It has been found that leucocytes possess receptor sites for glucagon and glucagon was shown to increase during bacterial infection. To verify the interconnection between glucagon, leucocytes and bacterial infection we studied the effect of glucagon on superoxide generation and second messenger transduction in PMNs. We found that glucagon could not stimulate chemiluminescence by itself but it could enhance FMLP- but not PMA-induced chemiluminescence in a concentration (50-800 pg/ml) dependent manner. However, after incubation of PMNs with 10 microM of ST-638 (a tyrosine kinase inhibitor) the enhancement effect converted into inhibitory effect. We also found that glucagon treatment of PMNs increased both IP3 and cyclic AMP levels as second messengers. ST-638 greatly attenuated the IP3 increment in the glucagon-treated FMLP-stimulated PMNs. From these results we can conclude that glucagon could enhance superoxide generation from FMLP-stimulated PMNs by elevating IP3. Inhibition of IP3 increment by tyrosine kinase blockade uncover the inhibitory effect of the increasing cyclic AMP on superoxide production.
Insights
Glucagon enhances bacterial infection responses in white blood cells (leukocytes) by increasing a key signaling molecule. Tyrosine kinase inhibition reveals a complex interaction affecting superoxide production.
Area of Science:
- Immunology
- Cellular Signaling
- Biochemistry
Background:
- Leukocytes (white blood cells) have receptors for glucagon.
- Glucagon levels rise during bacterial infections.
- The precise role of glucagon in leukocyte function during infection is unclear.
Purpose of the Study:
- To investigate the effect of glucagon on superoxide generation in polymorphonuclear neutrophils (PMNs).
- To examine the role of second messengers in glucagon-mediated PMN responses.
- To understand the interplay between glucagon, tyrosine kinase, and PMN activation.
Main Methods:
- Assessed glucagon's effect on PMN chemiluminescence (superoxide generation).
- Investigated glucagon's impact on inositol trisphosphate (IP3) and cyclic AMP (cAMP) levels.
- Utilized ST-638, a tyrosine kinase inhibitor, to probe signaling pathways.
Main Results:
- Glucagon alone did not induce chemiluminescence but enhanced FMLP-induced, not PMA-induced, chemiluminescence.
- Glucagon increased intracellular IP3 and cAMP levels in PMNs.
- ST-638 reversed glucagon's enhancement to inhibition and attenuated IP3 increases.
Conclusions:
- Glucagon enhances FMLP-stimulated superoxide generation in PMNs primarily by elevating IP3.
- Tyrosine kinase inhibition unmasks an inhibitory effect of increased cAMP on superoxide production.
- Glucagon modulates PMN function through complex signaling pathways involving IP3 and cAMP.