The long-term objective of my laboratory is to study the role of monocytes and macrophages in human autoimmune and inflammatory diseases. A specific interest over the past few years has been the regulation of interleukin 1 (IL 1) production by human monocytes. During the course of these studies it was observed that monocytes cultured on a substrate of adherent IgG released an IL 1 inhibitory activity. This IL 1 inhibitor (IL 1-3inh) was =25 kD in size and it specifically blocked IL 1 stimulation of both immune and inflammatory cells. The mechanism of action of this IL 1-inh was shown to be inhibition of receptor binding of IL 1 alpha and beta. The hypothesis to be examined in these proposed experiments is that IL 1alpha/beta and IL 1-inh production by human monocytes are regulated separately. This hypothesis will be examined under five specific aims: 1) to determine whether IL 1 and IL 1-inh are produced simultaneously by the same cells; 2) to examine IL 1-inh production and IL 1-inh mRNA levels in vitro-derived macrophages from normal donors or arthritis patients or in synovial macrophages from arthritis patients; 3) to determine the effects of monocyte differentiating agents or of culture substrates on regulation of IL 1-inh production; 4) to determine the mechanisms of regulation of IL 1-inh production in human monocytes and macrophages; and 5) to examine the characteristics of binding of recombinant IL 1-inh to various human cells. The techniques to be utilized in these proposed studies include the measurement of IL 1alpha, IL 1beta and IL 1-inh protein levels in cell lysates and supernatants using specific ELISA's, and the determination of relative steady-state mRNA levels by in vitro hybridization. Additional techniques will include immunocytochemical localization, in situ hybridization, nuclear run-on, mRNA stability and in vitro translation. Antibodies specific to the IL 1-inh, cDNA probes and recombinant IL 1-inh molecules have been made available to me by collaborators for use in these experiments. IL 1 has been implicated as an important mediator of tissue destruction in a variety of human diseases. A molecule that specifically blocks receptor binding of IL 1 may have therapeutic potential in these diseases. These proposed studies should provide important information on the mechanisms of regulation of production of an IL 1 inhibitor by human monocytes and synovial macrophages.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
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General Medicine A Subcommittee 2 (GMA)
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University of Colorado Denver
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Banda, Nirmal K; Guthridge, Carla; Sheppard, Devon et al. (2005) Intracellular IL-1 receptor antagonist type 1 inhibits IL-1-induced cytokine production in keratinocytes through binding to the third component of the COP9 signalosome. J Immunol 174:3608-16
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