title: Interleukin 1 beta mediates stress-induced immunosuppression via corticotropin-releasing factor.
abstract: Intracerebroventricular (icv) infusion of human interleukin 1 beta (IL-1) into intact and adrenalectomized rats impairs immune function. Using antibody to IL-1 as well as an inhibitor of IL-1 action, we sought to determine if endogenous IL-1 in the central nervous system has a physiological role in mediating the immunosuppressive effects of stress. Compared with freely moving controls, rats given intermittent electric shock to the tail for 40 min exhibited a fall in T lymphocyte proliferation and natural killer (NK) cell cytotoxicity of 33% and 38%, respectively; however, when pretreated with icv human IL-1 monoclonal antibody, which significantly crossreacts with rat IL-1, the decrement was attenuated to 14.6% and 15%, respectively. When rats were pretreated with icv alpha-MSH, which blocks many IL-1 effects, shock-induced suppression of 42% in both T lymphocyte proliferation and NK cytotoxicity were blunted to 33% and 31%, respectively. Similar results were found in adrenalectomized rats. These findings suggest that endogenous IL-1 is a physiologically relevant mediator of the immune response to stress. As IL-1 has been reported to release CRF, which we have shown always plays a significant role in stress-induced immunomodulation, we then assessed the relationship of IL-1 and CRF in immunosuppression. Infusion of icv IL-1 caused a decrease of 35% in T lymphocyte proliferation and 34% in NK activity, but pretreatment with CRF antibody icv attenuated IL-1 suppression of T lymphocyte proliferation and NK activity to 10% and 8%, respectively. Comparable results were observed in adrenalectomized rats. These findings suggest that CRF antibody is able to block the immunosuppressive effects of IL-1. To further examine the interaction of CRF in mediating stress-induced immunosuppression, we found that animals pretreated with icv CRF antibody, shocked and then given icv IL-1, had a decrement in T lymphocyte proliferation and NK cytotoxicity of 24% and 21%, respectively, demonstrating that the immunosuppressive effect of icv IL-1 is blocked when central CRF has been neutralized by prior administration of icv CRF antibody. In contrast, animals pretreated with icv IL-1 antibody, shocked and then given icv CRF, had decrements of 38% and 40%, respectively, showing that icv CRF does act even when central IL-1 has been neutralized by prior administration of icv IL-1 antibody. Thus, we conclude there is a sequential relationship between two of the known mediators of stress-induced immunosuppression, with release of central IL-1 followed by that of CRF.
authors.affiliation: Department of Medicine, New York University Medical Center, New York 10016.
authors.forename: A
authors.initials: A
authors.lastname: Saperstein
authors.forename: H
authors.initials: H
authors.lastname: Brand
authors.forename: T
authors.initials: T
authors.lastname: Audhya
authors.forename: D
authors.initials: D
authors.lastname: Nabriski
authors.forename: B
authors.initials: B
authors.lastname: Hutchinson
authors.forename: S
authors.initials: S
authors.lastname: Rosenzweig
authors.forename: C S
authors.initials: CS
authors.lastname: Hollander
mesh_terms: D000818:Animals; D000906:Antibodies / Q000276:immunology; D003346:Corticotropin-Releasing Hormone / Q000276:immunology / Q000502:physiology*; D004597:Electroshock; D007108:Immune Tolerance; D007375:Interleukin-1 / Q000494:pharmacology*; D007694:Killer Cells, Natural / Q000276:immunology; D008213:Lymphocyte Activation; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D013312:Stress, Physiological / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology; D000521:alpha-MSH / Q000494:pharmacology
chemical_list: D000906:Antibodies; D007375:Interleukin-1; D000521:alpha-MSH; D003346:Corticotropin-Releasing Hormone