Interleukin 1 induces interleukin 1: I. Induction of circulating interleukin 1 in rabbits in vivo and in human mononuclear cells in vitro

C. A. Dinarello, T. Ikejima, S. J.C. Warner, S. F. Orencole, G. Lonnemann, J. G. Cannon, P. Libby

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Abstract

Interleukin 1 (IL-1) plays an important role in host defense mechanisms by increasing body temperature, inducing the synthesis of a variety of lymphokines and hepatic acute phase proteins and acting as a chemoattractant for lymphocytes. However, in some microenvironments such as injured tissue or joint spaces, elevated IL-1 levels may contribute to pathologic processes, for example, proliferation and fibrosis of tissue involved in pannus formation as well as degradation of matrix and abnormal tissue architecture. To investigate potential mechanisms that may lead to excessive production of IL-1, we have examined the ability of IL-1 to participate in an amplification event by inducing its own gene expression leading to synthesis of biologically active IL-1. When injected into rabbits, recombinant human IL-1-α induced biphasic fevers, and during the second temperature elevation 3 hr later, a circulating pyrogenic material was detected by passive transfer of plasma to other rabbits. Induction of the biphasic fever was not caused by endotoxin contamination of the recombinant IL-1. The 3-hr circulating pyrogen was heat-labile and was not residual injected IL-1-α. Chromatographic separation of this plasma and biologic assay suggested that it was new IL-1 of rabbit origin. We next incubated human blood mononuclear cells with recombinant IL-1-α and measured the intracellular and extracellular levels of IL-1 by bioassay using the D10.G4.1 murine T cell line. In order to control for the carryover of recombinant IL-1-α used to stimulate the mononuclear cells (MNC), we used neutralizing antibodies that were specific for IL-1-α or IL-1-β. The results of these neutralizations showed that recombinant human IL-1-α induces the synthesis of IL-1-β in human MNC in vitro. These results were verified with a radioimmunoassay specific for IL-1-β. At concentrations of 100 ng/ml, IL-1-α induced prostaglandin E2 production in the MNC culture, and this was associated with decreased production of immunoreactive IL-1-β. Adding indomethacin to the cultures prevented the decreased production of IL-1-β induced by high concentrations of IL-1-α. Using non-adherent MNC, we observed an increase in IL-1-β as well as IL-1-α mRNA after 4 hr of exposure to recombinant IL-1-α. These results demonstrate that IL-1-α induces biologically active and immunoreactive IL-1-β from MNC in vitro and that the same concentrations of IL-1-α induce gene expression for both forms of IL-1. These studies suggest that IL-1 participates in an amplification event that is negatively influenced by its ability to induce prostaglandin E2 synthesis. These results may have clinical implications because they suggest that cyclo-oxygenase inhibitors, which are often administered to reduce IL-1-mediated inflammation, may also interfere with an intrinsic ability of IL-1 to down-regulate its own amplification.

Original languageEnglish (US)
Pages (from-to)1902-1910
Number of pages9
JournalJournal of Immunology
Volume139
Issue number6
StatePublished - Nov 24 1987

ASJC Scopus subject areas

  • Immunology

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    Dinarello, C. A., Ikejima, T., Warner, S. J. C., Orencole, S. F., Lonnemann, G., Cannon, J. G., & Libby, P. (1987). Interleukin 1 induces interleukin 1: I. Induction of circulating interleukin 1 in rabbits in vivo and in human mononuclear cells in vitro. Journal of Immunology, 139(6), 1902-1910.