Modulation of interleukin-1 receptors in the brain-endocrine-immune axis by stress and infection.
We summarize data from some of our recent studies on in vitro and in vivo modulation of interleukin-1 (IL-1) receptors in the mouse brain-endocrine-immune axis by stress and infection. Ether-laparotomy stress in mice resulted in a selective increase in pituitary IL-1 receptors and a significant decrease in pituitary receptors for corticotropin-releasing factor (CRF), a major regulator of the endocrine response to stress. Intraperitoneal injection of rat/human CRF mimicked the effects of stress and resulted in a dramatic increase in [125I]IL-1alpha binding in the pituitary; [125I]IL-1alpha binding in the hippocampus, spleen, and testis was unaffected by stress or CRF treatment. Glucocorticoid treatment with dexamethasone alone did not alter [125I]IL-1alpha binding but significantly inhibited CRF-induced upregulation of IL-1 receptors in the pituitary. The intracellular mechanism(s) involved in stress and CRF-induced upregulation of IL-1 receptors in the pituitary gland were examined by evaluating the effects of treatment of AtT-20 mouse pituitary corticotroph cells with a variety of neuroendocrine mediators of stress. CRF, forskolin, and isoproterenol (beta2 adrenergic receptor agonist) produced dose-dependent increases in cAMP production and [125I]IL-1alpha binding. In contrast, somatostatin and dexamethasone significantly inhibited CRF-stimulated increase of cAMP production and [125I]IL-1alpha binding, suggesting a primary role for cAMP in the regulation of pituitary IL-1 receptors. Next, we investigated the modulation of IL-1beta levels and IL-1 receptors following infection of mice with the endotoxin, lipopolysaccharide (LPS). Acute administration of low doses of endotoxin (30 mu g LPS/mouse) dramatically increased IL-1beta levels and reciprocally decreased [125I]IL-1alpha binding in peripheral tissues (pituitary, testis, liver, and spleen) but not in brain (hippocampus). This effect appeared to be dose related since higher doses of endotoxin (300 mu g LPS/mouse) significantly decreased [125I]IL-1alpha binding in both peripheral tissues and brain. Endotoxin induced modulation of the IL-1 system was also dependent on the treatment regimen since two low-dose LPS injections (at 0 and 12 h) increased IL-1beta concentrations and decreased [125I]IL-1alpha binding in both central and peripheral tissues. These data provide further support for a role for IL-1 in coordinating brain-endocrine-immune responses to stress and infection.
Takao
T
T
Second Department of Internal Medicine, Kochi Medical School, Nankoku, Japan.
Hashimoto
K
K
De Souza
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EB
D018685:Anesthetics, Inhalation / Q000009:adverse effects; D000818:Animals; D005576:Colforsin / Q000494:pharmacology; D003346:Corticotropin-Releasing Hormone / Q000494:pharmacology; D000242:Cyclic AMP / Q000502:physiology; D003907:Dexamethasone / Q000494:pharmacology; D004731:Endotoxins / Q000494:pharmacology; D004986:Ether / Q000009:adverse effects; D005786:Gene Expression Regulation / Q000187:drug effects; D006624:Hippocampus / Q000737:chemistry* / Q000187:drug effects; D006801:Humans; D007239:Infections / Q000503:physiopathology*; D007375:Interleukin-1 / Q000494:pharmacology; D007545:Isoproterenol / Q000494:pharmacology; D007813:Laparotomy / Q000009:adverse effects; D008099:Liver / Q000737:chemistry / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015213:Neuroimmunomodulation / Q000502:physiology; D010902:Pituitary Gland / Q000737:chemistry* / Q000187:drug effects; D010911:Pituitary Neoplasms / Q000473:pathology; D051381:Rats; D018019:Receptors, Corticotropin-Releasing Hormone / Q000096:biosynthesis / Q000235:genetics; D017472:Receptors, Interleukin-1 / Q000096:biosynthesis* / Q000235:genetics; D011994:Recombinant Proteins / Q000494:pharmacology; D013004:Somatostatin / Q000494:pharmacology; D013154:Spleen / Q000737:chemistry / Q000187:drug effects; D013312:Stress, Physiological / Q000503:physiopathology*; D013737:Testis / Q000737:chemistry / Q000187:drug effects; D014407:Tumor Cells, Cultured
D018685:Anesthetics, Inhalation; D004731:Endotoxins; D007375:Interleukin-1; D018019:Receptors, Corticotropin-Releasing Hormone; D017472:Receptors, Interleukin-1; D011994:Recombinant Proteins; D004986:Ether; D005576:Colforsin; D013004:Somatostatin; C044101:endotoxin, Escherichia coli; D003907:Dexamethasone; D003346:Corticotropin-Releasing Hormone; D000242:Cyclic AMP; D007545:Isoproterenol