The regulatory effects of cytokines on the induction of a peripheral immunologic tolerance in mice.
Previous reports have demonstrated that injection of rIL-1 alpha into mice abrogates the ability of deaggregated human gamma-globulin (HGG) to induce a state of antigen specific immunologic tolerance in vivo. Our results demonstrate that human rIL-1 beta and a bioactive nonapeptide of human IL-1 beta inhibit the induction of tolerance to HGG suggesting that IL-1 affects tolerance induction through a noninflammatory mechanism of action because the immunoactive nonapeptide possesses only immunomodulatory properties. Further, TNF-alpha but not IL-6, cytokines with many bioactivities in common with IL-1, was found to inhibit the induction of tolerance. Therefore, it appears unlikely that IL-6 plays a role in the pathway by which either IL-1 or TNF-alpha interferes with tolerance induction. Although IL-2, IL-4, and IFN-gamma were incapable of directly affecting the induction of tolerance to HGG, it was determined that IL-4 and IFN-gamma were capable of inhibiting the ability of IL-1 to abrogate tolerance induction. It has been suggested that IL-1 induces the generation of endogenous IL-1 in vivo. Further, it has been demonstrated that IFN-gamma as well as IL-4 inhibits the synthesis of IL-1. Inasmuch as IL-4 and IFN-gamma inhibit the ability of IL-1 to abrogate tolerance induction, it appears that it is the endogenously generated IL-1 that interferes with tolerance induction. It was also determined that neither IL-4 nor IFN-gamma inhibits the activity of IL-1 which is consistent with results reported by others. Thus, results presented here suggest that the inhibition of tolerance induction to HGG by IL-1 may involve the stimulation of endogenous IL-1 synthesis.
Department of Immunology, Research Institute of Scripps Clinic, La Jolla, CA 92037.
L C
LC
Gahring
W O
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Weigle
D000595:Amino Acid Sequence; D000818:Animals; D001685:Biological Factors / Q000494:pharmacology*; D016207:Cytokines; D005260:Female; D007108:Immune Tolerance / Q000187:drug effects*; D066298:In Vitro Techniques; D007371:Interferon-gamma / Q000494:pharmacology; D007375:Interleukin-1 / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D015847:Interleukin-4 / Q000494:pharmacology; D015850:Interleukin-6 / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D008808:Mice, Inbred CBA; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000494:pharmacology; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D005719:gamma-Globulins / Q000276:immunology
D001685:Biological Factors; D016207:Cytokines; D007375:Interleukin-1; D015850:Interleukin-6; D009842:Oligopeptides; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D005719:gamma-Globulins; D015847:Interleukin-4; D007371:Interferon-gamma