Interleukin 1 And Its Receptors

Teresa Krakauer, Department of Immunology and Molecular Biology, US Army Medical Research Institute of Infectious Diseases, Frederick, Maryland, USA

Joost J Oppenheim, Laboratory of Molecular Immunoregulation, National Cancer Institute, Frederick, Maryland, USA

Interleukin 1 (IL-1) was originally described by Gery and Waksman in 1971 as a macrophage-derived, 'lymphocyte-activating factor' (LAF) with comito-genic effects on thymocytes and T cells. Subsequent studies revealed structural and biochemical similarities of LAF to other partially characterized mediators such as endogenous pyrogen, leukocytic endogenous mediator, B cell-activating factor, mononuclear cell factor, catabolin and osteoclast-activat-ing factor. In 1979, the term IL-1 was proposed for the putative protein with all these pleiotropic activities.

The bioassay for LAF could be performed in multi-well assay plates and was sufficiently sensitive to effectively monitor purification and molecular cloning studies aimed at identifying IL-1. Before the advent of recombinant DNA technology, efforts to biochemically purify human IL-1 detected the existence of high (31 kDa) and low (17kDa) molecular forms of LAF/IL-1, representing aggregated and mature forms, respectively. In 1984-1985, by using a combination of hydrophobic chromatography, gel filtration, isoelectrofocusing and high performance liquid chromatography, the low molecular weight protein was shown to consist of two molecules with different isoelectric points, pi 5.4 and pi 6.8. Cloning of cDNA for human IL-1 by Auron and colleagues in 1984 and March and coworkers in 1985 identified two distinct proteins with IL-1 activities, IL-la with a pi of 5.4 and IL-1(3 with a pi of 6.8. All the aforementioned biological activities of IL-1 were manifested by recombinant IL-1. A third member of the IL-1 family, IL-1 receptor antagonist (IL-lra), was cloned by Eisenberg and colleagues in 1990. IL-lra was initially detected as an IL-1 inhibitor found naturally in the urine of patients with fever or myelo-monocytic leukemia. IL-lra acts as a specific antagonist of IL-la and IL-1 (J by binding to IL-1 receptors without transducing a signal.

An endogenous mediator of host inflammatory responses, IL-1 also participates in regulating specific immune responses by enhancing the growth and differentiation of both B and T lymphocytes. It is active over low concentrations of 10 '' to 10 " m. When locally produced by stimulated cells, IL-1 acts in an autocrine or paracrine manner to augment early nonspecific inflammatory and later specific immune responses. When released in larger quantities into the circulation, IL-1 acts systemically to exert its endocrine effects such as activation of the fever center, the hypothalamus-pituitary-adrenal (HPA) axis and in inducing acute phase proteins.

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