Interleukin-1 receptor antagonist circulates in experimental inflammation and in human disease.

Interleukin-1 receptor antagonist (IL-1ra) is a 22-Kd protein that shares homology with IL-1 beta, binds to the IL-1 receptor, but has no known agonist properties. This inhibitor appears to be the first cytokine whose sole function is to block the actions of another cytokine. Exogenous IL-1ra administration has been shown to reduce mortality in experimental septic shock. We now report that IL-1ra is endogenously produced and circulates in experimental inflammation and in clinical disease. After experimental endotoxemia in human volunteers, IL-1ra concentrations increase from a baseline concentration of 460 +/- 200 pg mL-1 to 14,870 +/- 290 pg mL-1 at 3 hours (P less than .05). IL-1ra is also detectable in all plasma samples from critically ill patients with a mean concentration of 8,680 +/- 2,060 pg mL-1 (range 320 to 55,370 pgs mL-1). In nonhuman primates, Escherichia coli septic shock induces elevated plasma levels of IL-4ra (P less than .05). However, in animals that eventually succumb to septic shock, Il-1ra appears in quantities presumed inadequate to block the pathologic sequelae associated with high IL-1 beta levels. The findings suggest that IL-1ra may play a role in modulating the systemic host responses to a variety of nonlethal disease states by altering the balance between cytokines and their antagonists.     

Different receptor mechanisms mediate the pyrogenic and behavioral effects of interleukin 1.

Interleukin 1 (IL-1) is a cytokine released during immune activation that mediates the host's response to infection and inflammation. Peripheral and central injections of IL-1 induce fever and sickness behavior, including decreased food motivation and reduced interest in social activities. To determine the receptor mechanisms responsible for these effects, rats were injected with IL-1 receptor antagonist (IL-1ra), an endogenous cytokine that acts as a pure antagonist of IL-1 receptors. IL-1ra blocked the increased body temperature and oxygen consumption induced by injection of recombinant human IL-1 only when both cytokines were administered i.p. In contrast, i.p. or intracerebroventricular administration of IL-1ra blocked the depressive effect of IL-1 beta on food-motivated behavior and social exploration when this cytokine was administered by the same route as the antagonist. In addition, intracerebroventricular IL-1ra blocked the reduction in social exploration produced by i.p. IL-1 beta but had only partial antagonist effects on the decrease in food-motivated behavior induced by i.p. IL-1 beta. In each case, the dose of IL-1ra was 100- to 1000-fold in excess of the biologically active dose of IL-1. These results suggest that the receptor mechanisms that mediate the behavioral and pyrogenic effects of IL-1 are heterogeneous.     

Immunotherapeutic implication of IL-6 blockade

IL-6 is a cytokine featuring redundancy and pleiotropic activity. While IL-6 contributes to host defense against acute environmental stress, continuous IL-6 production plays a significant pathological role in various autoimmune and chronic inflammatory diseases. To counter this drawback, tocilizumab, a humanized anti-IL-6 receptor antibody, was developed. Clinical trials have verified the efficacy of tocilizumab for patients with rheumatoid arthritis, Castleman's disease and systemic juvenile idiopathic arthritis, resulting in approval of this innovative biologic for their treatment. Moreover, a considerable number of case reports and pilot studies have indicated the beneficial effects of tocilizumab on other autoimmune and chronic inflammatory diseases. Further clinical studies to evaluate the efficacy and safety of tocilizumab for these diseases are essential.     

Absence of donor Th17 leads to augmented Th1 differentiation and exacerbated acute graft-versus-host disease

Th17 is a newly identified T-cell lineage that secretes proinflammatory cytokine IL-17. Th17 cells have been shown to play a critical role in mediating autoimmune diseases such as EAE, colitis, and arthritis, but their role in the pathogenesis of graft-versus-host disease (GVHD) is still unknown. Here we showed that, in an acute GVHD model of C57BL/6 (H-2(b)) donor to BALB/c (H-2(d)) recipient, IL-17(-/-) donor T cells manifested an augmented Th1 differentiation and IFN-gamma production and induced exacerbated acute GVHD. Severe tissue damage mediated by IL-17(-/-) donor T cells was associated with increased Th1 infiltration, up-regulation of chemokine receptors by donor T cells, and enhanced tissue expression of inflammatory chemokines. Administration of recombinant IL-17 and neutralizing IFN-gamma in the recipients given IL-17(-/-) donor cells ameliorated the acute GVHD. Furthermore, the regulation of Th1 differentiation by IL-17 or Th17 may be through its influence on host DCs. Our results indicate that donor Th17 cells can down-regulate Th1 differentiation and ameliorate acute GVHD in allogeneic recipients, and that treatments neutralizing proinflammatory cytokine IL-17 may augment acute GVHD as well as other inflammatory autoimmune diseases.     

Effect of interleukin-1 (IL-1) blockade on cytokine synthesis: I. IL-1 receptor antagonist inhibits IL-1-induced cytokine synthesis and blocks the binding of IL-1 to its type II receptor on human monocytes.

Interleukin-1 (IL-1) induces IL-1, tumor necrosis factor alpha (TNF alpha), and IL-6 gene expression and synthesis in a variety of cells. In this study, we investigated the ability of human recombinant IL-1 receptor antagonist (IL-1ra) to inhibit IL-1-induced cytokine production in human peripheral blood mononuclear cells (PBMC) and isolated monocytes. IL-1ra alone at concentrations as high as 1 microgram/mL did not induce IL-1 alpha, IL-1 beta, TNF alpha, or IL-6 synthesis. Suppression of IL-1-induced IL-1, TNF alpha, or IL-6 synthesis was dose-dependent (P less than or equal to .0001). At a twofold molar excess, IL-1ra inhibited IL-1-induced IL-1 or TNF alpha synthesis by 50% (P less than .01); an equimolar concentration of IL-1ra inhibited synthesis of these two cytokines by over 20% (P less than .05). A 10-fold molar excess of IL-1ra over IL-1 beta reduced IL-1 beta-induced IL-1 alpha by 95% (P = .01) and IL-1 alpha-induced IL-1 beta by 73% (P less than .01). IL-1ra added to PBMC 8 hours after stimulation with IL-1 beta was still able to inhibit IL-1 alpha, TNF alpha, and IL-6 synthesis (P less than or equal to .01). A similar reduction in IL-1 beta-induced IL-1 alpha was observed when IL-1 beta was removed from the cultures after 8 hours of stimulation (P less than .05), suggesting a prolonged presence of IL-1 or restimulation of IL-1 receptors on monocytes is required for the induction of cytokines. In elutriated monocytes, a 10-fold molar excess of IL-1ra reduced IL-1 beta-induced IL-1 alpha by 82% (P less than .05), TNF alpha by 64% (P = .05), and IL-6 by 47% (P less than .05). 125I-IL-1 beta was bound to purified monocytes, cross-linked, and immunoprecipitated. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis showed a band at 85 Kd corresponding to the 68-Kd IL-1 receptor type II (IL-1RtII). Excess unlabeled IL-1 beta or IL-1ra blocked the binding of 125I-IL-1 beta to the IL-1RtII. We conclude that IL-1ra inhibits IL-1-induced cytokine synthesis and competes with IL-1 for the IL-1RtII on human monocytes.     

Cytokine Polymorphisms and Susceptibility to Severe Infectious Diseases

Cytokines are key regulators of the host response to infection, controlling the inflammatory reaction which is an essential component of the defense mechanisms. The major importance of these proteins in the pathogenesis and outcome of infectious diseases has been clearly demonstrated. In humans, there is increasing evidence that the host's cytokine response is genetically determined and that the genetic variability of cytokines underlies the complexity of interindividual differences in the immune response to micro organism invasions. We review the influence of host cytokine gene on the susceptibility to and the severity of parasitic, bacterial and viral infections. Proinflammatory cytokine polymorphisms are discussed in detail because of their importance in the course of severe infections such as meningococcal disease, cerebral malaria and septic shock. Genetic variants of the IL-10 gene, an antiinflammatory cytokine appear to be responsible for an uncontrolled and intense CARS and may have also dramatic consequences as an overwhelming inflammatory response. Our greater understanding of the genetic factors that influence mortality and morbidity of infectious diseases will permit identification of genomic markers which may be required for risk stratification of patients targeted for novel immunomodulatory treatments helping clinicians to select the most appropriate treatment options for their patients.     

Serum IL-1ra is elevated in lepromatous leprosy patients

Patterns of production of specific cytokines are accepted as standards for T-lymphocyte subsets in diseases caused by intracellular parasites. These lymphocyte subsets (Th1 and Th2) have been associated with the different poles of the leprosy spectrum. Lepromatous leprosy (LL) onset correlates with cytokines produced by Th2 cells on the grounds of the patient's poor cellular immune response, i.e., interleukin 2 (IL-2) and gamma interferon (IFN-gamma) deficiency. On the other hand, tuberculoid leprosy (TL) has been associated with a Th1 response. Moreover, pro-inflammatory cytokines like IL-1 beta and tumor necrosis factor-alpha (TNF-alpha) play a major role in chronic inflammatory pathologies being IL-1ra and TNF-alpha soluble receptors, natural counterbalancing inhibitors. In light of this background, we decided to measure serum levels of IL-1 beta, IL-1ra, TNF-alpha and IL-6 in LL and TL patients, and we also studied the production in vitro of Th1 (IFN-gamma, IL-2), Th2 (IL-4, IL-10) and TNF-alpha cytokines. Our data showed that IL-1ra is highly elevated in sera from LL patients; there were no differences in Th2 cytokine levels and there were diminished levels in Th1 cytokines.     

The proinflammatory cytokines interleukin-1 and tumor necrosis factor and treatment of the septic shock syndrome

Treating the septic shock syndrome with antibodies that block only endotoxin has its limitations. Other targets for treating septic shock include neutralizing antibodies to the complement fragment C5a, platelet-activating factor antagonists, and blockade of endothelial cell leukocyte adhesion molecules. Specific blockade of the proinflammatory cytokines interleukin-1 (IL-1) or tumor necrosis factor (TNF) reduces the morbidity and mortality associated with septic shock. Moreover, blocking IL-1 and TNF likely has uses in treating diseases other than septic shock. Use of neutralizing antibodies to TNF or to IL-1 receptors have reduced the consequences of infection and inflammation, including lethal outcomes in animal models. The IL-1 receptor antagonist, a natural-occurring cytokine, blocks shock and death due to Escherichia coli and ameliorates a variety of inflammatory diseases. Soluble TNF and IL-1 surface receptors, which bind their respective cytokines, also ameliorate disease processes. Current clinical trials are evaluating the safety and efficacy of these anticytokine therapies either alone or together.     

Localization of interleukin-1 receptor antagonist mRNA in rat brain.

Interleukin-1 (IL-1) is an inflammatory peptide hormone, with potent neuroendocrine effects. IL-1 stimulates the central nervous system production of corticotropin-releasing hormone (CRH), growth hormone (GH), thyroid-stimulating hormone (TSH), and somatostatin, and inhibits the secretion of prolactin and luteinizing hormone (LH). Interleukin-1 receptor antagonist (IL-1ra) is a novel cytokine, recently purified, characterized, and cloned. IL-1ra is a pure endogenous antagonist of IL-1:IL-1 function is modulated not only by local levels of IL-1, but also by the levels of IL-1ra. We have localized by in situ hybridization histochemistry IL-1ra mRNA in rat brain, in areas of importance to neuroendocrine function, such as the paraventricular nucleus (PVN) of the hypothalamus, hippocampus, as well as cerebellum. These findings indicate that IL-1ra is produced in brain in areas of relevance to the regulation of neuroendocrine function and suggest that IL-1ra may modulate the neuroendocrine effects of IL-1.