Abstract
Bradykinin (BK) has been reported to be a mediator of brain damage in acute insults. Receptors for BK have been identified on microglia, the pathologic sensors of the brain. Here, we report that BK attenuated lipopolysaccharide (LPS)-induced release of tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta from microglial cells, thus acting as an anti-inflammatory mediator in the brain. This effect was mimicked by raising intracellular cAMP or stimulating the prostanoid receptors EP2 and EP4, while it was abolished by a cAMP antagonist, a prostanoid receptor antagonist, or by an inhibitor of the inducible cyclooxygenase (cyclooxygenase-2). BK also enhanced formation of prostaglandin E(2) and expression of microsomal prostaglandin E synthase. Expression of BK receptors and EP2/EP4 receptors were also enhanced. Using physiological techniques, we identified functional BK receptors not only in culture, but also in microglia from acute brain slices. BK reduced LPS-induced neuronal death in neuron-microglia co-cultures. This was probably mediated via microglia as it did not affect TNF-alpha-induced neuronal death in pure neuronal cultures. Our data imply that BK has anti-inflammatory and neuroprotective effects in the central nervous system by modulating microglial function.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Alprostadil / metabolism
-
Animals
-
Animals, Newborn
-
Anti-Inflammatory Agents / immunology
-
Anti-Inflammatory Agents / metabolism
-
Anti-Inflammatory Agents / pharmacology
-
Bradykinin / immunology
-
Bradykinin / metabolism*
-
Bradykinin / pharmacology
-
Cells, Cultured
-
Coculture Techniques
-
Cyclic AMP / metabolism
-
Cytokines / immunology
-
Cytokines / metabolism*
-
Cytoprotection / immunology*
-
Encephalitis / immunology
-
Encephalitis / metabolism*
-
Encephalitis / physiopathology
-
Gliosis / chemically induced
-
Gliosis / immunology
-
Gliosis / metabolism
-
Interleukin-1beta / immunology
-
Interleukin-1beta / metabolism
-
Lipopolysaccharides
-
Mice
-
Mice, Inbred C57BL
-
Microglia / immunology
-
Microglia / metabolism*
-
Nerve Degeneration / immunology
-
Nerve Degeneration / metabolism*
-
Nerve Degeneration / physiopathology
-
Organ Culture Techniques
-
Rats
-
Rats, Wistar
-
Receptors, Bradykinin / drug effects
-
Receptors, Bradykinin / metabolism
-
Receptors, Prostaglandin E / antagonists & inhibitors
-
Receptors, Prostaglandin E / metabolism
-
Receptors, Prostaglandin E, EP4 Subtype
-
Tumor Necrosis Factor-alpha / immunology
-
Tumor Necrosis Factor-alpha / metabolism
Substances
-
Anti-Inflammatory Agents
-
Cytokines
-
Interleukin-1beta
-
Lipopolysaccharides
-
Ptger4 protein, mouse
-
Receptors, Bradykinin
-
Receptors, Prostaglandin E
-
Receptors, Prostaglandin E, EP4 Subtype
-
Tumor Necrosis Factor-alpha
-
Cyclic AMP
-
Alprostadil
-
Bradykinin