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)

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-1 beta 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-1 alpha or IL-1 beta and IL-2, the surface expression of IL-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 10(6) cells/ml. The cells were pretreated for 2 h with hrIL-1ra (0.025-250 ng/ml), treated with LPS (10 ng/ml), and IL-1 alpha and IL-1 beta 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-stimulated PBMC pretreated with 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-1 alpha, IL-1 beta, 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.

Early induction of IL-1 receptor antagonist (IL-1Ra) in infants and children undergoing surgery

“…Considering the key role played by IL-l in influencing the growth and differentiation of immunoeompetent lymphocytes, it seems reasonable to assume that the immunologieal depression often observed after major surgery might be related to the IL-IRa response whieh we have shown to be induced after surgery. A reeent report ofthe ability of IL-IRa to down-regulate IL-la, IL-2, the IL-2 reeeptor (CD25) expression, and lectin-stimulated lymphocyte proliferation [36], would lend further support lo its potential role in modulating the immune response. However, other in vitro studies have shown that the proliferative responses of T lymphocytes to antigens or mitogens were unaffected by IL-I Ra [37].…”

Inflammasome activation in NADPH oxidase defective mononuclear phagocytes from patients with chronic granulomatous disease

“…Consistently, IL-1 levels were substantially reduced ex vivo by inhibiting caspase-1 with a specific inhibitor or by blocking IL-1 signaling with the naturally occurring IL-1Ra (supplemental Figures 1,3). 10,11 Based on these findings, we wondered whether the hyperinflammatory condition in symptomatic CGD patients involves a deregulation of IL-1 and analyzed monocytes from patients with granulomatous colitis, a common gastrointestinal manifestation in CGD that involves inflammation in the absence of infectious agents. 5 Intriguingly, both, unstimulated and LPS-stimulated monocytes from symptomatic CGD patients showed strongly increased caspase-1 and IL-1 levels, indicating that caspase-1 is active during severe colitis in CGD despite the loss of phagocyte oxidase function ( Figure 2E, supplemental Figure 4).…”

Epithelial barrier and oral bacterial infection

“…In 1981, a human thymocyte suppressor was detected that later was shown to specifically inhibit , and also to be a natural inhibitor of , interleukin‐1. It inhibits interleukin‐1‐mediated responses, such as the production of collagenase and prostaglandin E 2 , the expression of interleukin‐2 receptors in T‐cells and neutrophil migration . This inhibitor, termed interleukin‐1 receptor antagonist, competes with interleukin‐1 for binding to interleukin‐1 receptors without inducing typical interleukin‐1‐related cellular responses .…”