IL-18 in inflammatory and autoimmune disease

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Cellular and Molecular Life Sciences

Review

IL‑18 in inflammatory and autoimmune disease Saikiran K. Sedimbi · Thomas Hägglöf · Mikael C. I. Karlsson 

Received: 8 April 2013 / Revised: 4 July 2013 / Accepted: 11 July 2013 © Springer Basel 2013

Abstract  Inflammation serves as the first line of defense in response to tissue injury, guiding the immune system to ensure preservation of the host. The inflammatory response can be divided into a quick initial phase mediated mainly by innate immune cells including neutrophils and macrophages, followed by a late phase that is dominated by lymphocytes. Early in the new millennium, a key component of the inflammatory reaction was discovered with the identification of a number of cytosolic sensor proteins (Nod-like receptors) that assembled into a common structure, the ‘inflammasome’. This structure includes an enzyme, caspase-1, which upon activation cleaves proforms of cytokines leading to subsequent release of active IL-1 and IL-18. This review focuses on the role of IL-18 in inflammatory responses with emphasis on autoimmune diseases. Keywords  IL-18 · Canonical & non-canonical IL-18 production · Autoimmune and inflammatory diseases

Introduction Cytokines comprise a vital system of signaling proteins necessary for communication between cells. From the perspective of the immune system, they are indispensable for the development and maturation of immune cells,

S. K. Sedimbi (*) · T. Hägglöf · M. C. I. Karlsson (*)  Department of Medicine‑Solna, Translational Immunology Unit, Karolinska Institutet, Karolinska University Hospital Solna, L2:04, 171 76 Stockholm, Sweden e-mail: [email protected] M. C. I. Karlsson e-mail: [email protected]

regulation of responses, both activating and tolerogenic, and response against antigens and clearance of dying cells. For many years, cytokines were mainly grouped under T helper (Th) subclasses based on the type of T cell responses they participated in. However, with the discovery of cytokines, such as IL-18 and IL-33, that are not loyal to activation of Th-subsets, a broader view is needed to understand the diversity cytokines bring to health and disease.

Discovery The cytokine IL-18 was initially identified as a protein in sera from mice treated with bacterium Propionibacterium acnes and challenged with LPS, which induces interferon γ (IFNγ) in naïve spleen cells [1]. Subsequently, IFNγinducing factor (IGIF) was cloned from livers of these mice. The IGIF protein, mainly produced by Kuppfer cells as a 192 amino acids (aa) precursor, is cleaved to a mature protein of 157 aa [2]. Recombinant IGIF was also found to induce T cell proliferation and augment natural killer (NK) cell cytotoxic activity in primary spleen cells. Close to the discovery of murine IGIF, human IGIF was cloned (using murine IGIF cDNA as a probe) and expressed in E. coli [3]. Human IGIF similarly induced IFNγ in peripheral blood mononuclear cells (PBMCs). Though structurally similar to IL-1 family cytokines, IGIF is functionally and structurally distinct, an