title: Role of central beta-adrenergic receptors in regulating proinflammatory cytokine responses to a peripheral bacterial challenge.
abstract: Elevation of proinflammatory cytokines in the brain have potent effects on altering physiological, behavioral, and cognitive processes. The mechanism(s) by which brain cytokines are induced during a peripheral immune challenge remains unclear since microorganisms/cytokines do not cross the blood-brain barrier (BBB). Recent studies indicate that central beta-adrenergic receptors (beta-ADRs) may mediate brain interleukin-1beta (IL-1) production. This has direct implications for the production of brain cytokines during a peripheral immune response since peripheral pathogens and cytokines rapidly stimulate brainstem catecholamine neurons via peripheral nerves and circumventricular pathways. Studies here examine the role of central beta-ADRs in regulating brain cytokine production following peripheral Escherichia coli (E. coli) challenge. Rats were centrally administered propranolol (beta-ADR antagonist) or vehicle followed by peripheral E. coli or saline and sacrificed 6h later for measurement of cytokines. Pre-treatment with propranolol completely blocked the induction of brain IL-1 following E. coli. Surprisingly, central propranolol also attenuated E. coli-induced peripheral cytokines. To examine whether the attenuated peripheral cytokine response following central propranolol administration was due leakage of propranolol into the general circulation and blockade of peripheral beta-blockade, nadolol (beta-ADR antagonist that does not cross the BBB) was administered peripherally prior to E. coli. Nadolol administration did not block central cytokine production following E. coli, but instead enhanced both peripheral and central proinflammatory cytokine production. Furthermore, central administration of isoproterenol (beta-ADR agonist) results in a time-dependent increase in brain IL-1 production. These data demonstrate central beta-ADRs may play a critical role to induce brain IL-1, while peripheral beta-ADRs inhibit cytokine response to bacterial challenge.
authors.affiliation: Biological Sciences Department, Kent State University, Kent, OH 44242, USA. Electronic address: jjohns72@kent.edu.
authors.forename: John D
authors.initials: JD
authors.lastname: Johnson
authors.affiliation: Department of Integrative Physiology & Center for Neuroscience, University of Colorado, Boulder, CO 80309-0354, USA.
authors.forename: Valerie
authors.initials: V
authors.lastname: Cortez
authors.affiliation: Department of Integrative Physiology & Center for Neuroscience, University of Colorado, Boulder, CO 80309-0354, USA.
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Kennedy
authors.affiliation: Department of Integrative Physiology & Center for Neuroscience, University of Colorado, Boulder, CO 80309-0354, USA.
authors.forename: Teresa E
authors.initials: TE
authors.lastname: Foley
authors.affiliation: Department of Integrative Physiology & Center for Neuroscience, University of Colorado, Boulder, CO 80309-0354, USA.
authors.forename: Hugo
authors.initials: H
authors.lastname: Hanson
authors.affiliation: Department of Integrative Physiology & Center for Neuroscience, University of Colorado, Boulder, CO 80309-0354, USA.
authors.forename: Monika
authors.initials: M
authors.lastname: Fleshner
mesh_terms: D000318:Adrenergic beta-Agonists / Q000008:administration & dosage / Q000494:pharmacology; D000319:Adrenergic beta-Antagonists / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism* / Q000382:microbiology; D016207:Cytokines / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D004927:Escherichia coli Infections / Q000382:microbiology / Q000503:physiopathology*; D018836:Inflammation Mediators / Q000378:metabolism; D007375:Interleukin-1 / Q000378:metabolism; D007545:Isoproterenol / Q000008:administration & dosage / Q000494:pharmacology; D008297:Male; D008845:Microinjections; D009248:Nadolol / Q000008:administration & dosage / Q000494:pharmacology; D011433:Propranolol / Q000008:administration & dosage / Q000494:pharmacology; D051381:Rats; D011916:Rats, Inbred F344; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*
chemical_list: D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; D016207:Cytokines; D018836:Inflammation Mediators; D007375:Interleukin-1; D011943:Receptors, Adrenergic, beta; D009248:Nadolol; D011433:Propranolol; D007545:Isoproterenol