Inhibition of Interleukin‐1 (Alpha and Beta), Interleukin‐2 Secretion and Surface Expression of Interleukin‐2 Receptor (IL‐2R) by a Novel Cytokine Interleukin‐1 Receptor Antagonist (IL‐lra)

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Abstract
IL‐1 is a mediator of the acute inflammatory response and plays a key role in influencing growth and differentiation of immunocompetent lymphocytes. It can enhance transcription and secretion of the T‐cell growth factor interleukin‐2 (IL‐2) and can stimulate the expression of membrane receptors for IL‐2. However, the regulation and control of IL‐1 activities are poorly understood. Recently an IL‐1 inhibitor, interleukin‐1 receptor antagonist (IL‐1ra), has been described and cloned. This protein is a monokine originally found in the urine of febrile patients and in supernatants of human monocytes adhering to an IgG‐coated surface, with an approximate molecular weight of 17 kDa, which is similar to IL‐1β but having no IL‐1‐like activity and antagonizing IL‐1 by binding to its cell surface receptor.These studies have examined some biological properties of hrIL‐1ra, such as its effects on the secretion of IL‐1α or IL‐1β and IL‐2, the surface expression of 1L‐2R and DNA synthesis by peripheral blood mononuclear cells (PBMC). PBMC from normal volunteers were separated and used at a concentration of 2.5 x 106 cells/ml. The cells were pretreated for 2h with hrIL‐1ra (0.025‐250 ng/ml), treated with LPS (10 ng/ml), and IL‐1α and IL‐1β secretion were determined by an ELISA method. In addition the influence of hrIL‐1ra (25 ng/ml) on IL‐2 generation was determined. In another set of experiments, flow cytometric analysis with an anti‐CD25 monoclonal antibody was determined on PHA‐stimulaled PBMC pretreated wilh hrIL‐1ra (2 h) and cultured for 48 h. The inhibition by hrIL‐1ra of IL‐2R expression was dose‐dependent and when hrIL‐1ra was used at 250 ng/ml the IL‐2R was completely abolished. Lymphocyte DNA synthesis calculated from the net uptake of [3H]‐thymidine (3H‐TdR) was also inhibited by hrIL‐1ra (0.025‐25 ng/ml). In this report we found that hrIL‐1ra inhibits, in a dose‐dependent manner, the secretion of IL‐1α, IL‐1β, IL‐2, the surface expression of IL‐2R and 3H‐TdR incorporation in PBMC in vitro. These data suggest a new biological activity of hrIL‐1ra and further extend the immunomodulatory potential and significance of this new cytokine. The action of IL‐1ra on modulating the synthesis of IL‐1 may be of paramount importance in the regulation of these effects.