Treatment of Inflammatory Diseases with IL-1 Blockade.

BACKGROUND: Autoinflammatory diseases are distinct from autoimmune diseases. Whereas autoinflammatory diseases are due to dysfunctional T-cells and B-cells, autoinflammatory diseases are due to overproduction of macrophage cytokines particularly interleukin-1 beta (IL-1ß). A causative role for IL-1 in autoinflammatory diseases is derived from clinical studies blocking the IL-1 receptor or neutralizing monoclonal antibodies or soluble receptors. METHODS: A review was performed of clinical trials in autoinflammatory diseases using the IL-1 receptor antagonist (anakinra), the soluble IL-1 receptor (rilonacept), antibodies to IL-1ß (canakinumab, gevokizumab) and anti-IL-1α (xilonix). FINDINGS: Anakinra blocks the IL-1 Receptor type 1 (IL-1R1) and therefore blocks the activities of both IL-1α and IL-1ß. Off-label use of anakinra is common for a broad spectrum of inflammatory diseases. Neutralization of IL-1ß is used to treat hereditary autoinflammatory diseases but also atherosclerosis. Rilonacept reduces arterial wall inflammation in patients with chronic kidney disease. Neutralization of IL-1α has prolonged life in patients with advanced metastatic colorectal cancer. Compared to other cytokine blocking therapies, reducing the activities of IL-1 has an excellent safety record. CONCLUSIONS: Blocking IL-1 therapies can be used to treat a wide-spectrum of acute and chronic inflammatory diseases.

The Role of Interleukin-1 in the Pathogenesis of Cancer and its Potential as a Therapeutic Target in Clinical Practice.

Interleukin-1 (IL-1) has long been known to be a key mediator of immunity and inflammation. Its dysregulation has been implicated in recent years in tumorigenesis and tumor progression, and its upregulation is thought to be associated with many tumors. Overexpression of the IL-1 agonists IL-1α and IL-1ß has been shown to promote tumor invasiveness and metastasis by inducing the expression of angiogenic genes and growth factors. IL-1 blockers such as anakinra and canakinumab are already approved and widely used for the treatment of some autoimmune and autoinflammatory diseases and are currently being tested in preclinical and human clinical trials for cancer therapy. In this paper we review the most recent discoveries regarding the association between IL-1 dysregulation and cancer and present the novel IL-1 blockers currently being tested in cancer therapy and their corresponding clinical trials.