Interleukin-1, Interleukin-1 Receptors and Interleukin-1 Receptor Antagonist

IL-1 (IL-1α or IL-1β) is the prototypic “multifunctional” cytokine. Unlike the lymphocyte and colony stimulating growth factors, IL-1 affects nearly every cell type, and often in concert with other cytokines or small mediator molecules. Although some lymphocyte and colony stimulating growth factors may be therapeutically useful, IL-1 is a highly inflammatory cytokine and the margin between clinical benefit and unacceptable toxicity in humans is exceedingly narrow. In contrast, agents that reduce the production and/or activity of IL-1 are likely to have an impact on clinical medicine. In support of this concept, there is growing evidence that the production and activity of IL-1, particularly IL-1β, are tightly regulated events as if nature has placed specific “road blocks” to reduce the response to IL-1 during disease. In addition to controlling gene expression, synthesis and secretion, this regulation extends to surface receptors, soluble receptors and a receptor antagonist. Investigators have studied how production of the different members of the IL-1 family is controlled, the various biological activities of IL-1, the distinct and various functions of the IL-1 receptor (IL-1R) family and the complexity of intracellular signaling. Mice deficient in IL-1β, IL-1β converting enzyme (ICE) and IL-1R type I have also been studied. Humans have been injected with IL-1 (either IL-1α or IL-1β) for enhancing bone marrow recovery and for cancer treatment. The IL-1 specific receptor antagonist (IL-IRa) has also been tested in clinical trials.     

Interleukin-11

Interleukin-11 (IL-11) is a cytokine which interacts with a variety of haemopoietic and non-haemopoietic cell types. Recombinant human IL-11 (rhIL-11; oprelvekin) is produced in Escherichia coli and differs from the naturally occurring protein only in the absence of the amino-terminal proline residue. In synergy with other factors, rhIL-11 stimulates the growth of myeloid, erythroid, and megakaryocyte progenitor cells in vitro. In vivo, rhIL-11 is active in mice, rats, dogs, guinea pigs, hamsters and non-human primates, where the principal activity measured was stimulation of megakaryocytopoiesis and thrombopoiesis. rhIL-11 has shown benefit in 2 clinical trials by significantly reducing severe chemotherapy-induced thrombocytopenia. In addition to its thrombopoietic activity, rhIL-11 has also shown activity in models of acute gastrointestinal mucosal damage. rhIL-11 enhanced survival in mice following cytoablative therapy and in a hamster model of chemotherapy-induced oral mucositis, where treatment with rhIL-11 was associated with decreased mucosal damage, accelerated healing and reduced numbers of deaths. rhIL-11 is currently in clinical trials for the treatment of chemotherapy-induced mucositis. In rat models of acute colonic injury and inflammatory bowel disease, rhIL-11 treatment reduced intestinal mucosal damage and alleviated clinical signs. rhIL-11 has direct effects on activated macrophages to reduce the production of pro-inflammatory mediators. In animal models of endotoxaemia, rhIL-11 treatment reduced serum levels of pro-inflammatory cytokines and blocked hypotension. rhIL-11 increased survival in models of Gram-negative sepsis and toxic shock. Based on these studies, rhIL-11 is currently in clinical trials for treatment of Crohn's disease. Other inflammatory conditions are being further evaluated. Mechanistically, rhIL-11 functions at many levels to control inflammation, ameliorate tissue damage and maintain haemostasis in the face of trauma or infection. rhIL-11 has direct effects on hepatocytes, inducing the production of acute phase reactant proteins, haem oxygenase and tissue inhibitor of metalloproteinase-1 (TIMP-1). TIMP-1 expression can also be induced in synoviocytes and chondrocytes by treatment with rhIL-11. rhIL-11 administration has been associated with increased plasma levels of von Willebrand factor and fibrinogen. rhIL-11 treatment potentially offers multiple benefits for cancer chemotherapy patients, such as prevention of thrombocytopenia, gastrointestinal epithelial protection and subsequent reduction of mucositis, and amelioration of inflammatory complications. In addition, rhIL-11 is being evaluated further in the treatment of inflammatory disorders such as inflammatory bowel disease, rheumatoid arthritis and sepsis.     

Interleukin-18

Interleukin-18 (IL-18), a recently described member of the IL-1 cytokine superfamily, is now recognized as an important regulator of innate and acquired immune responses. IL-18 is expressed at sites of chronic inflammation, in autoimmune diseases, in a variety of cancers, and in the context of numerous infectious diseases. This short review will describe the basic biology of IL-18 and thereafter address its potential effector and regulatory role in several human disease states including autoimmunity and infection. IL-18, previously known as interferon-gamma (IFN-gamma)-inducing factor, was identified as an endotoxin-induced serum factor that stimulated IFN-gamma production by murine splenocytes [(1) ]. IL-18 was cloned from a murine liver cell cDNA library generated from animals primed with heat-killed Propionibacterium acnes and subsequently challenged with lipopolysaccharide [(2) ]. Nucleotide sequencing of murine IL-18 predicted a precursor polypeptide of 192 amino acids lacking a conventional signal peptide and a mature protein of 157 amino acids. Subsequent cloning of human IL-18 cDNA revealed 65% homology with murine IL-18 [(3) ] and showed that both contain an unusual leader sequence consisting of 35 amino acids at their N terminus.     

Interleukin-3

Synopsis

Interleukin-3 is an early- and late-acting haemopoietic growth factor which promotes the proliferation and differentiation of multilineage and single lineage committed progenitor cells. It also has modulatory effects on mature cells, including basophils, monocytes and eosinophils. Interleukin-3 stimulates the proliferation of bone marrow and peripheral blood progenitor cells and increases bone marrow cellularity, causing a shift of haemopoiesis to the left, with a subsequent increase in the proportion of immature haemopoietic cells and in numbers of megakaryocytes and eosinophils. Interleukin-3 also potentiates granulocyte-macrophage colony-stimulating factor- (GM-CSF) and granulocyte colony-stimulating factor- (G-CSF) mediated mobilisation of peripheral blood progenitor cells from the bone marrow to the blood. Preliminary clinical trials show that recombinant human interleukin-3 (referred to as interleukin-3) reduces haematological toxicity in patients following standard- or high-dose chemotherapy with or without autologous bone marrow transplantation. The duration of neutropenia was reduced and importantly, platelet numbers were generally increased such that the duration of thrombocytopenia was also reduced in the majority of studies. There was a trend towards a lower requirement for platelet transfusions in treatment cycles that included interleukin-3 compared with those that did not, and the need to postpone further chemotherapy cycles due to prolonged haematological toxicity was reduced with interleukin-3. Sequential combination therapy with interleukin-3 followed by recombinant GM-CSF appears to further enhance haemopoietic recovery in these indications. Other potential applications of interleukin-3 include disease states with intrinsic bone marrow dysfunction, such as myelodysplasia and aplastic anaemia. Thus, the ability of interleukin-3 to reduce both neutropenia and thrombocytopenia in preliminary studies suggests that this cytokine will be useful, either alone or in sequential combination with other cytokines, for the treatment of haematological toxicity associated with chemotherapy, following bone marrow transplantation, and in the treatment of haemopoietic stem cell disorders.

Pharmacological Properties

Interleukin-3 (multipotential colony-stimulating factor) is a haemopoietic growth factor, secreted predominantly by activated T-helper lymphocytes. It stimulates the proliferation of early haemopoietic progenitor cells in the bone marrow, including colony-forming unit (CFU)-granulocyte-erythroid-macrophage-megakaryocyte (CFU-GEMM), CFU-granulocyte-macrophage (CFU-GM), burst-forming unit-erythroid (BFU-E), CFU-eosinophil (CFU-Eo), CFU-megakaryocyte (CFU-Meg), and CFU-basophil (Bas) cells. It also stimulates the proliferation of peripheral blood progenitor cells in vitro. Bone marrow cellularity is increased by interleukin-3 in patients with normal haemopoiesis, bone marrow failure or myelodysplastic syndrome, and there is a shift of haemopoiesis to the left, increasing the proportion of immature haemopoietic progenitor cells and the numbers of eosinophils and megakaryocytes. The cytokine also affects cells at later stages of maturation including basophils, eosinophils and monocytes. It is unclear whether interleukin-3 can induce the mobilisation of peripheral blood progenitor cells when administered alone; however, it potentiates the effect of recombinant granulocyte-macrophage colony-stimulating factor (rGM-CSF) and recombinant granulocyte colony-stimulating factor (rG-CSF). In vitro studies indicate that interleukin-3 enhances the cytotoxic effects of cytarabine (ara-C) on acute myeloid leukaemia cells; however, its efficacy in humans in this setting remains to be determined. Data on the pharmacokinetic properties of recombinant human interleukin-3 are limited. Peak plasma concentrations are reached within 2 to 4 hours following subcutaneous administration of interleukin-3 and are dose-proportional. The plasma elimination half-life is 1.3 to 3.3 hours following subcutaneous administration and 0.4 to 1 hour following intravenous administration. The apparent systemic clearance of interleukin-3 is 0.3 L/h/kg, irrespective of the route of administration or dosage.

Clinical Potential

Recombinant human interleukin-3 (referred to as interleukin-3) has shown clinical efficacy in reducing haematological toxicity following standard- and high-dose chemotherapy treatment regimens in small phase I/II clinical trials reported to date. A daily dosage of 5 to 10 μg/kg, administered either subcutaneously or by continuous intravenous infusion, caused a significant increase in neutrophil and platelet counts after chemotherapy and reduced the duration of neutropenia and thrombocytopenia compared to that observed in control chemotherapy cycles in which interleukin-3 was not given. A reduction in the need to postpone further chemotherapy due to prolonged haematological toxicity was observed with interleukin-3 treatment, and the number of patients requiring platelet transfusions was also reduced. Sequential administration of interleukin-3 followed by rGM-CSF or rG-CSF may further reduce myelosuppression. Interleukin-3 also enhanced platelet and neutrophil recovery following autologous bone marrow transplantation, and in patients with bone marrow failure. Its relative benefits in reducing myelosuppression compared with those of other cytokines remain unclear. Preliminary findings indicate that sequential combination therapy with interleukin-3 and rGM-CSF may be beneficial compared with monotherapy with either agent in these indications. In addition, interleukin-3/rG-CSF-induced mobilisation of peripheral blood progenitor cells prior to apheresis and re-transplantation, or in vitro incubation of patients’ bone marrow cells with interleukin-3 and rGM-CSF or rG-CSF prior to transplantation, both appeared to enhance marrow recovery of platelet numbers. These findings require further investigation. Interleukin-3 may also offer some clinical benefit to patients with myelodysplastic syndromes in that their leucocyte counts are increased. However, it has shown only transient effects, if any, on platelet counts in these patients. Initial findings indicate that patients with aplastic anaemia may also derive some clinical benefit from treatment with interleukin-3. Further study of its efficacy relative to that of other agents in these indications is warranted.

Tolerability

There are few tolerability data available for interleukin-3. While adverse events have been reported frequently, they have been generally tolerable at dosages ≤ 10 μg/kg/day. Influenza-like symptoms (myalgia, arthralgia, fatigue), headache, and low grade fever have occurred most frequently. Severe headache occurring at dosages > 10 μg/kg/day was often a dose-limiting event. Other adverse events have included nausea, vomiting, skin rash, mild local erythema at the injection site, flushing, oedema, facial erythema, diarrhoea, rigors, malaise and dyspnoea; these were generally mild and resolved at the end of treatment. The tolerability profile of interleukin-3 appeared similar when the drug was administered prior to or following chemotherapy, and during combined sequential treatment with rGM-CSF or rG-CSF.

Dosage and Administration

In clinical trials, interleukin-3 has been administered once daily by subcutaneous injection or by continuous intravenous infusion. For the treatment of myelosuppression following chemotherapy, ≥ 5 μg/kg/day for 7 to 14 days appears to be an effective dosage, and 10 μg/kg/day has shown efficacy in patients following autologous bone marrow transplantation. A lower dosage of interleukin-3 2.5 μg/kg/day for 10 days followed by rGM-CSF therapy has also shown efficacy in the bone marrow transplantation setting. Interleukin-3 30 to 500 μg/m²/day for 15 days induced a haematological response in patients with bone marrow failure, and 250 to 500 μg/m²/day for 14 to 15 days induced a response in patients with myelodysplastic syndromes or aplastic anaemia.     

Interleukin-10

Interleukin-10 (IL-10) is a potent anti-inflammatory and immunosuppressive cytokine secreted by several cell types. Most anti-inflammatory effects of IL-10 are caused by its ability to deactivate macrophages and monocytes, whereas its immunosuppressive properties are due to functional inhibition of both antigen-presenting cells and T cells. On the other hand, IL-10 also exerts immunostimulatory effects, especially on B cells, CD8+ cytotoxic T cells and natural killer cells. In vivo administration of recombinant IL-10 (rIL-10) efficiently prevents experimental septic shock induced by endotoxin, staphylococcal superantigen or cecal ligation and puncture, as well as experimental autoimmune diseases mediated by T helper type 1 (T(H)1) cells and other inflammatory disorders. rIL-10 exerts paradoxical effects in cancer models, where it promotes tumour rejection, probably due to its stimulatory properties on cytotoxic cells. On the other hand, rIL-10 increases the severity of experimental infections caused by fungi or bacteria, and enhances systemic autoimmune features in mice with spontaneous lupus syndrome. Although the therapeutic potential of rIL-10 in human diseases seems promising, the multiple facets of rIL-10 in experimental immunopathology indicate that the success of clinical trials with rIL-10 will depend both on the appropriate selection of the patient populations to be treated and on the early detection of possible adverse effects.     

Interleukin-17

The particular interest of IL-17, a homodimeric cytokine of about 32kDa, is the strict requirement for an activation signal to induce its expression from a rather restricted set of cells, human memory T cells or mouse αβTCR⁺CD4^?CD8^? thymocytes. In contrast with the tightly controlled expression pattern of this gene, the IL-17 receptor, a novel cytokine receptor, is ubiquitously distributed but apparently more abundant in spleen and kidney. In addition to its capture by the T lymphotropic Herpesvirus Saimiri (HVS), this cytokine is inducing the secretion of IL-6, IL-8, PGE₂, MCP-1 and G-CSF by adherent cells like fibroblasts, keratinocytes, epithelial and endothelial cells. IL-17 is also able to induce ICAM-1 surface expression, proliferation of T cells, and growth and differentiation of CD34⁺ human progenitors into neutrophils when cocultured in presence of irradiated fibroblasts. In vitro, IL-17 synergjzes with other proinflammatory signals like TNFα for GM-CSF induction, and with CD40-ligand for IL-6, IL-8, RANTES and MCP-1 secretion from kidney epithelial cells. In vivo, injection of IL-17 induces a neutrophilia, except in IL-6-KO mice. The involvement of IL-17 in rejection of kidney graft has also been demonstrated. The role of this T cell secreted factor in various inflammatory processes is presently investigated.     

Interleukin-13

Gastrointestinal nematode parasites are one of the most prevalent types of infection worldwide. Evidence from both laboratory and human systems indicates that when resistance is evident immunity is mediated by effector mechanisms controlled by Thelper 2 type responses. Moreover, more recent evidence implicates a central role for interleukin 13. We raise the possibility that gut dwelling nematodes may have been an important driving force in the development of Th 2 responses involving IL-13. Moreover, that these parasites have evolved a variety of strategies to avoid destruction and to regulate any potential pathology associated with chronic infection.     

Interleukin-16

Interleukin 16 (IL-16) was initially described in 1982 as the first T cell chemoattractant. Through interaction with CD4, IL-16 has now been characterized as a chemoattractant for a variety of CD4+ immune cells. Recent in vivo studies have more fully characterized IL-16 as an immunomodulatory cytokine that contributes to the regulatory process of CD4+ cell recruitment and activation at sites of inflammation in association with asthma and several autoimmune diseases. Since its cloning in 1994, IL-16 structure and function have been studied extensively. This review addresses the current data regarding IL-16 protein and gene structure; the expanding list of cells capable of generating IL-16; the direct interaction of IL-16 with its receptor, CD4; and the functional bioactivities of IL-16 as they relate to inflammation and HIV-1 infection. In addition, potential therapeutic modalities for IL-16 relating to inflammation and immune reconstitution in HIV-1 infection are also discussed.     

Interleukin-10 Directly Inhibits the Interleukin-6 Production in T-Cells

IL-6 is a potent regulator of T-cell activation, proliferation and differentiation. Since IL-10 inhibits cytokine production by T cells, the effect of IL-10 on IL-6 production by T cells was investigated. IL-6 production by purified monocytes or T cells was detected from cell-free culture supernatants by ELISA after stimulation of the cells with LPS or an anti-CD3 monoclonal antibody for 3 days. Although the main source of IL-6 are LPS activated monocytes (29.6 × lOng/ml), T cells secreted sufficiently high levels of IL-6 (790 × 200pg/ml) to stimulate the high affinity IL-6 receptor. IL-10 decreased anti-CD3 induced IL-6 mRNA expression by up to 80%. In addition, IL-10 significantly inhibited IL-6 release from T-cells. Highly purified, anti-CD3 activated T-cells secreted 600 × 150pg/ml IL-6 compared to 21 × 2pg/ml IL-6 following addition of IL-10 (10ng/ml; P <0.001). FACS analysis revealed a monocyte contamination of the T-cell preparations of less than 0.5%. In addition, no IL-1 production was detectable. Thus, in our experiments the effect of TL-10 on IL-6 production was independent of the presence of monocytes. Finally, inhibition of IL-6 production was not reversed by IL-2 (100U/ml). In conclusion, IL-10 suppressed the synthesis of IL-6 by T-cells via a monocyte-and IL-2-independeni mechanism. These results may help to understand the complex regulation of T-cell mediated cytokine production by IL-10.     

Interleukin-5.

Interleukin-5 is a dimeric cytokine that controls the differentiation of B cells into antibody-secreting cells as well as inducing the growth of Ly-1(CD5)+ B cells and B-cell tumors. It also has a major role of the growth and differentiation of eosinophils. Rapid progress has been made during the last year in the delineation of the structure and activities of interleukin-5, and the molecular nature of its functional receptors. Interleukin-5 exerts pleiotropic activities on various target cells through a high-affinity receptor which is composed of two different polypeptide chains, alpha and beta. The alpha chain binds interleukin-5 with low affinity and the beta chain has been identified as the interleukin-3 receptor-like protein and is also the beta chain of the granulocyte-macrophage colony stimulating factor receptor.     

Interleukin-2.

In the past year there have been significant advances in understanding the role of interleukin-2. Its role in the activation of T cells by antigen-presenting cells, the structure-activity relationships between interleukin-2 and its receptor and the subsequent signaling have all become clearer. The creation of mice with a specific defect in the interleukin-2 gene has given us a clearer idea of its role in vivo. Recent studies also suggest that interleukin-2 may finally find a role in immunotherapy.     

Interleukin-10.

Despite the short history of interleukin-10, accumulated evidence indicates that this interleukin plays a major role in suppressing immune and inflammatory responses. Yet interleukin-10 also maintains cell viability and acts as a cofactor to promote the growth of lymphoid and myeloid cells in vitro. Here we review the present knowledge on the structure and function of interleukin-10.     

Interleukin-1 and Interleukin-1 Receptor Antagonist in Systemic Lupus Erythematosus

Interleukin-1 (IL-1) is thought to play an important role in the immunopathology of systemic lupus erythematosus (SLE). IL-1 receptor antagonist (IL-lra) exhibits a dose-responsive inhibition of IL-1 effects, and Fcr receptors play a key role in IL-lra production. To clarify the relationship between IL-1, IL-1 receptor antagonist (IL-lra) production, and Fcr receptors in SLE, fifteen untreated lupus patients (9 females and 6 males) were evaluated. IL-1 and IL-lra production from both monocytes and neutrophils was determined by both a murine thymocyte proliferation assay and ELISA. The expression of Fcr receptors on both monocytes and polymorphonuclear cells was measured by flow cytometry. There was no significant difference between IL-1 beta and IL-lra production from ex vivo monocytes between lupus patients and normals. However, serum IL-lra was significantly higher in lupus patients than in normals. The expression of FcrRII (CD32) on monocytes was lower in lupus patients than in normals. There was no correlation between the expression of FcrRII and the serum immune complexes; the production of IL-lra and the expression of CD32, serum immune complex levels, and serum IgG. Both serum IL-ra and the production of IL-lra had no correlation to SLEDAI, C3, C4, Clq, or ESR. These observations suggest that although IL-1 and IL-lra may not play a major role in the initiation of pathogenesis of lupus, the low FcrRII expression in lupus may reflect low immune complex clearance and contribute to disease pathogenesis.