Treatment of Inflammatory Diseases with IL-1 Blockade

Abstract

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-1β). 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-1β (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-1β. Off-label use of anakinra is common for a broad spectrum of inflammatory diseases. Neutralization of IL-1β 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.

Keywords: anakinra; canakinumab; cancer; innate immunity; rilonacept; xilonix.

Figure 1.. The 3 subfamilies of the IL-1 family.

The lengths of the precursors are shown with the number of amino acids indicated at the end of each cytokine. The location of IL-1 family consensus sequence AXD is indicated in each precursor. In consensus sequence AXD, the A is an aliphatic amino acid, X is any amino acid and then D is always aspartic acid. The aspartic acid D is not the aspartic acid for the recognition of caspase-1 cleavage. Nine amino acids preceding the AXD site is a vertical bar. The vertical bar indicates the location of the optimal N-terminus. The processing enzymes of the precursors that result in an optimal N-terminus differ for each member. Some members of the IL-1 family have more than one AXD site thus creating an alternative N-terminus, for example IL-37 (137). The N-terminus affects the dimensional structure of the cytokine and therefore receptor binding and activity (138). In the case of IL-1β, nine amino acids preceding the AXD site is the caspase-1 cleavage site at amino acid 117. The IL-1 family members with proinflammatory properties are indicated by a red circle whereas a green circle represents cytokines that are anti-inflammatory. IL-1Ra is a unique member of the IL-1 family and highly homologous to IL-1β. IL-1Ra precursor has a classic signal peptide, is processed in the Golgi and readily secreted. There is an intracellular form of the IL-1Ra generated by alternate splicing. Intracellular IL-1Ra plays a role inside the cell (139). Because IL-1Ra has a signal peptide and is readily secreted, there is no AXD site.