1. Introduction 2. Interleukin-1 and inflammation 3. Immuno-inflammatory pathways and interleukin-1 in depression 4. IL-1 in translational models 6. Working mechanisms of IL-1 blockade 7. Expert opinion: targeting IL-1 in depression Review Targeting IL-1 in depression Michael Maes, Cai Song † & Raz Yirmiya † Chinese Academy Engineering Institute for the Development of Endangered Medicinal Resources in Southwest China, Guangxi Botanic Garden of Medicinal Plants, Guangxi, P. R. China Introduction: Depression is associated with inflammation, Th1 and Th17 responses, oxidative and nitrosative stress (O&NS), autoimmune responses against neoantigenic determinants, and neuroprogression (i.e., neurodege- neration, impaired plasticity and reduced neurogenesis). These pathways involve increased monocytic activation and interleukin-1 (IL-1) levels. Areas covered: This review will highlight the putative role of IL-1 in depression and the potential use of IL-1 signaling blockade as a treatment of depression. Electronic databases, i.e., Scopus, PUBMED and Google Scholar were employed using keywords: depression, depressive-like, interleukin-1, and interleukin-1 receptor antagonist (IL-1RA). Expert opinion: Ample studies show that depression is accompanied by increased levels of IL-1 and IL-1RA, which attenuates the pro-inflammatory activities of IL-1. In some, but not all studies, antidepressant treatment decreased IL-1b levels. In translational models, IL-1b administration elicits depressive-like behaviors, neuroinflammation and neuroprogression, whereas treatment with IL-1RA yields antidepressant-like effects and attenuates neuroprogression. Anakinra, an IL-1RA, targets not only IL-1 signaling, but also Th1, Th17, O&NS and neuroprogressive pathways and therefore may be advanced to clinical Phase-II trials in depression due to medical conditions associated with an elevated IL-1/IL-1RA ratio. Keywords: antidepressants., cytokines, depression, inflammation, interleukin-1 Expert Opin. Ther. Targets (2012) 16(11):1097-1112 1. Introduction Recent conceptualizations of depression have centered on immuno-inflammatory pathways, including inflammation, cell-mediated immune activation, oxidative and nitrosative stress (O&NS), decreased levels of antioxidants, mitochondrial dysfunctions and neuroprogression [1-6]. Neuroprogression is defined as a progres- sive, stage related process of neurodegeneration, reduced neuronal plasticity and neurogenesis [2,3,7]. One inflammatory process that is frequently upregulated in depression is monocyte/macrophage activation with increased levels of interleukin-1 (IL-1) [8]. This pro-inflammatory cytokine drives immune pathways and may cause neuroinflammation and neuroprogression. By inference, IL-1 may be involved in the pathophysiology of depression [1,3]. Here, we review the putative role of IL-1 in depression and the potential use of IL-1 blockade as a treatment of depression. Methods: Electronic databases, i.e., Scopus, Pubmed and Google Scholar were employed as sources for this review using the keywords: depression, depressive-like, interleukin-1, and interleukin-1 receptor antagonist. 2. Interleukin-1 and inflammation 2.1 Inflammation, immune activation and autoimmunity Inflammation consists of a response in the cytokine network, an acute phase response in the liver and activation of complement cascades. Macrophage and 10.1517/14728222.2012.718331 © 2012 Informa UK, Ltd. ISSN 1472-8222 1097 All rights reserved: reproduction in whole or in part not permitted Expert Opin. Ther. Targets Downloaded from informahealthcare.com by Hebrew University on 11/24/12 For personal use only.