SurveyThe balance between IL-1 and IL-1Ra in disease
Introduction
The IL-1 family of molecules consists of two agonists, IL-1α and IL-1β, a specific receptor antagonist called IL-1Ra, and two different receptors, IL-1R type I (IL-1RI) and IL-1R type II (IL-1RII) [1], [2]. IL-1 plays an important role in host resistance against microorganisms that divide inside cells, such as mycobacteria or listeria. The IL-1 family is an important part of the innate immune system, which regulates functions of the adaptive immune system. The balance between IL-1 and IL-1Ra in local tissues influences the possible development of inflammatory disease and resultant structural damage. In the presence of an excess amount of IL-1, inflammatory and autoimmune diseases may develop in many organs such as the joints, lungs, gastrointestinal track, central nervous system (CNS), or blood vessels. Treatment of human disease with IL-1Ra has been carried out by injection of recombinant protein or using gene therapy approaches. This chapter will review background information on the members of the IL-1 family, the role of IL-1 and IL-1Ra in normal physiology and disease, and the results of clinical trials with administration of IL-1Ra in human disease.
Section snippets
Background on members of the IL-1 family
The cytokine now known as IL-1 was originally described as biological activities in cell supernatants or body fluids under names such as endogenous pyrogen, lymphocyte activating factor, mononuclear cell factor, and catabolin. The cDNAs for two forms of IL-1 were cloned in 1984 with expression of related molecules of 17 kDa termed IL-1α and IL-1β [1]. These proteins are synthesized as 31 kDa precursors in the cytoplasm of cells and lack leader sequences. In the human most pro-IL-1α is transmitted
Balance between IL-1Ra and IL-1 in normal physiology
The balance between IL-1Ra and IL-1 levels in local tissues influences the relative physiologic or pathophysiologic effects of IL-1. Upon injection of LPS into normal volunteers plasma concentrations of IL-1 peaked at 2 h at ∼80 pg/ml, followed by a peak of IL-1Ra concentrations at 3–6 h of ∼6400 pg/ml [26]. This almost 100-fold greater plasma concentration of IL-1Ra over IL-1 reflects primarily production of sIL-1Ra by the liver as an acute phase protein [27], [28], [29]. IL-1Ra levels are
IL-1 and IL-1Ra in disease
An important proinflammatory role for IL-1 in many human diseases has been described over the past 10 years. The balance between IL-1 and IL-1Ra has been extensively studied in a variety of experimental animal models of disease including arthritis, inflammatory bowel disease (IBD), granulomatous and fibrotic lung disorders, kidney diseases, diseases of the liver and pancreas, graft-versus-host disease (GVHD), leukemia and cancer, osteoporosis and diabetes, central nervous system diseases,
IL-1 in arthritis
An involvement of IL-1 in arthritis was implied by the studies of Fell and Jubb in 1977 [40] who described that cultured synovial tissue released a factor that activated chondrocytes, leading to proteoglycan degradation in adjacent cartilage pieces (Table 2). As bioassays and ELISAs for IL-1 were subsequently developed, numerous investigators described the presence of IL-1 in the synovial fluid of RA patients [41], [42], produced by synovial fluid monocytes in vitro [43], or produced by
IL-1Ra in arthritis
Extensive studies indicate the presence of IL-1Ra in the joints of rheumatoid patients, but the amounts produced are insufficient to inhibit the injurious effects of IL-1 (Table 3). IL-1Ra is present in the rheumatoid synovium, particularly in the lining layer cells and in the sublining area in a perivascular distribution within macrophages [58], [59], [60]. High levels of IL-1Ra were present in rheumatoid synovial fluid, produced by both neutrophils and macrophages [61], [62], [63]. The
Inflammatory bowel disease
The importance of the balance between IL-1 and IL-1Ra in IBD was first demonstrated in experimental animal models. Studies in immune complex-induced colitis in rabbits showed that IL-1 synthesis in the colon occurred early in the disease and IL-1 levels correlated with the degree of tissue inflammation [82]. IL-1Ra levels in the colon were elevated 10-fold above those of IL-1, preceding resolution of the inflammation in immune complex-induced colitis in rabbits [83]. The administration of
Pulmonary diseases
The roles of IL-1 and IL-1Ra also have been examined in a variety of experimental animal models of lung disease and in human pulmonary diseases. Local IL-1 production has been associated with fibrotic and infectious lung diseases, particularly with granuloma formation. Both IL-1- and TNF-α mediated inflammation and tissue destruction in immune complex-induced lung injury in rats, and treatment with IL-1Ra or antibodies to TNF-α decreased these effects [91]. Endogenous IL-1Ra also was shown to
Renal diseases
As in other organs, IL-1 has been implicated in the pathogenesis of immune, inflammatory, and fibrotic kidney diseases. Studies on glomerulonephritis induced in rats by injection of anti-glomerular basement membrane (GBM) antibodies indicated a differential local production of IL-1 and IL-1Ra within the kidney, suggesting the presence of an excess of IL-1 in the glomeruli [105]. Administration of IL-1Ra prevented the development of the disease and also reversed the progressive changes of the
Diseases of the liver and pancreas
The production of sIL-1Ra by hepatocytes in the liver as an acute phase protein is reviewed above. Thus, elevated levels of IL-1Ra are found in the circulation after surgery on the liver, following a variety of surgical procedures, or during inflammatory diseases of the liver. Antibodies neutralizing to IL-1Ra exacerbated bacterial-induced hepatitis in mice, again indicating an important anti-inflammatory role for endogenous IL-1Ra [116]. The serum ratio of IL-1Ra to IL-1 was higher in patients
Graft-versus-host disease
Both IL-1 and TNF-α are mediators of GVHD after bone marrow transplantation in both mice and humans [124]. Administration of IL-1Ra reduced the immunosuppression and mortality of GVHD across minor histocompatibility antigen differences in mice without impairing the engraftment of hematopoietic stem cells [125]. However, anti-cytokine treatment was less successful in GVHD across a major histocompatibility barrier in mice [126]. In a phase I/II open-label trial of IL-1Ra infusion in 17 patients
Leukemia and cancer
IL-1 and IL-1Ra have been invoked in a variety of human malignancies. Acute myeloblastic leukemia (AML) cells produce IL-1 as an autocrine growth factor; IL-1Ra mRNA is rarely present in AML cells and in vitro proliferation of AML cells was inhibited by added IL-1Ra. The bone marrow of AML patients contained more IL-1β and less IL-1Ra than normal cells, and sera from AML patients exhibited lower levels of IL-1Ra protein, suggesting that an imbalance between IL-1 and IL-1Ra may play role in the
Osteoporosis and diabetes
Members of the IL-1family have potent effects on calcification of bone. IL-1Ra completely inhibited the resorption and PGE2 production induced in bone by IL-1 in vitro [137]. In addition, bone loss induced in rats by ovariectomy was significantly reduced by the administration of IL-1Ra at the time of ovariectomy [138]. Further experiments indicated that IL-1Ra specifically blocked bone loss during estrogen deficiency by decreasing the IL-1-induced proliferation and differentiation of osteoclast
Diseases of the central nervous system
Extensive evidence indicates that both IL-1 and IL-1Ra are produced in the CNS and that the ratio between these two cytokines may influence the development of different diseases of the brain [148]. IL-1Ra in the circulation crossed the blood–brain barrier [149], and IL-1Ra was produced by both microglial and astroglial cells in areas of the brain important in the neuroendocrine effects of IL-1 [150]. IL-1 was released in the brain during hypoxia-ischemia injury induced by ligation of the
Infectious diseases
Both IL-1 and IL-1Ra are produced by human monocytes, macrophages, and neutrophils in a variety of different infections in animals or humans, primarily induced by LPS. In addition, the liver produces IL-1Ra in a delayed fashion after injection of LPS, contributing to the marked increase in circulating levels of this cytokine during infections [26], [27]. The ratio between IL-1 and IL-1Ra in local tissues may influence the course of different infectious diseases. For example, the spirochete
Role of IL-1Ra in endothelial cells and arterial diseases
The results of recent studies have implicated an imbalance between IL-1 and IL-1Ra in the pathophysiology of coronary artery disease. Endogenous production of IL-1β by coronary artery smooth muscle cells was shown to mediate post-transplant arteriopathy in piglets [171]. Treatment with IL-1Ra prevented fatty-streak formation in apolipoprotein E-deficient mice, suggesting a role for IL-1 in the initiation of atherosclerosis [172]. IL-1β production is upregulated in pig or rat coronary arteries
Role of intracellular IL-1Ra
At least two intracellular isoforms of IL-1Ra are produced by human epithelial cells, monocytes, macrophages, neutrophils and hepatocytes [21], [22], [23], [24], [25]. These molecules may play additional roles inside cells that may not involve binding to IL-1 receptors. Initial studies indicated that in malignant human ovarian epithelial cells expression of icIL-1Ra1 blocked cytokine-induced IL-8 and GRO expression by de-stabilizing their mRNA [180]. However, no further studies on this
IL-1Ra allelic polymorphisms and disease
An allelic polymorphism exists in intron 2 of the sIL-1Ra gene, or intron 3 of the extended gene containing the additional 5′ exon encoding icIL-1Ra1 [188]. This polymorphism consists of two to six numbers of an 86 bp tandem repeat, with allele A1 (IL1RN∗1) found in 73.6% of the normal population and allele A2 (IL1RN∗2) present in 21.4% [189]. IL1RN∗2 has been associated with a variety of human diseases, primarily of epithelial and endothelial cells (Table 5) [190]. In many of these diseases,
Treatment of human diseases with IL-1Ra
Clinical trials of recombinant human IL-1Ra in sepsis syndrome and in RA have been completed (Table 6). Studies in human volunteers showed that IL-1Ra administration improved the symptoms of mild endotoxemia but did not alter the hemodynamic, immunologic and metabolic responses [235]. An initial clinical trial of IL-1Ra infusion for 72 h in 99 patients with sepsis syndrome indicated a possible dose-dependent improvement in mortality at 28 days [236]. The results of a subsequent phase III
Gene therapy with IL-1Ra
The successful treatment of disease with recombinant IL-1Ra protein has led to the development of a variety of gene therapy approaches. Gene therapy was first performed by transducing cultured synovial cells ex vivo with the IL-1Ra cDNA in a retroviral vector; the cells then were injected back into the knee joint of the same rabbit [246]. These cells grew, expressed the IL-1Ra protein, and protected the joint from IL-1-induced leukocyte infiltration, synovial thickening, and proteoglycan loss
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