PERSPECTIVE www.SCIENCESIGNALING.org 2 October 2012 Vol 5 Issue 244 pe45 1 The idea that inflammatory processes con- tribute to brain-related pathologies, such as depressive disorders, has been gaining trac- tion, particularly because activation of the inflammatory immune response might also account for the frequent comorbidity that occurs between depression and heart dis- ease, metabolic syndrome, diabetes, auto- immune disorders, and stroke recovery (1, 2). This focus has increased further in light of the possibility that inflammatory factors might serve as biomarkers to predict the de- velopment of depression and its recurrence, as well as to predict the most efficacious treatments of depressive disorders (2). We address current issues linking inflammato- ry processes to growth factors and hence to depression, and the potential involvement of those processes in the comorbid condi- tions that have often been associated with depressive disorders (Fig. 1). The view that inflammatory factors con- tribute to depression was initially predi- cated on findings that circulating cyto- kines (signaling molecules of the immune system) and other inflammatory factors were increased in depressed patients. Fur- thermore, in rodents, inflammatory agents, such as lipopolysaccharide (LPS), elicited behaviors reminiscent of depression (1), and low doses of a bacterial endotoxin provoked low mood or fatigue in humans (3). These changes were accompanied by increased amounts of circulating interleu- kin-6 (IL-6) and tumor necrosis factor–α (TNF-α), increased amygdala neuronal activity in response to socially threatening stimuli, and a feeling of “social disconnec- tion” that could favor the evolution of de- pression (4). Particularly strong evidence for a cy- tokine/depression relationship came from studies showing that the administration of interferon-α (IFN-α) for the treatment of some cancers and hepatitis C was accom- panied by depression in about 50% of pa- tients, particularly those with a history of depression or with low concentrations of the serotonin (5-HT) precursor tryptophan (5). Moreover, in animal models of depres- sion, as well as in humans, antidepressants attenuated the depressive effects of IFN-α, and the positive effects of antidepressant treatments could be enhanced by adjunctive anti-inflammatory agents (5, 6). Several perspectives have been offered to account for how inflammatory fac- tors might promote brain neurochemical changes that lead to depression. In addi- tion to gaining limited access to the central nervous system (CNS) from the periphery, cytokines are produced in the brain by glial cells, and their production is increased in response to various insults, such as head in- jury, ischemia, and stroke (7), and by physi- cal or psychological stressors (8). Once increased, cytokines might have either posi- tive (neuroprotective) or negative (neurode- structive) actions, depending on their abun- dance. For instance, after ischemic stroke, depressive-like illness is common (9), and this condition is probably secondary to in- creased levels of cytokines. Indeed, a key feature of depression (anhedonia), reflected by reduced consumption of a favored food (sucrose), was elicited in animals models of ischemic stroke, which was attenuated by pretreatment with the IL-1 antagonist IL- 1ra (10), as were several behavioral chang- es ordinarily elicited by psychological and physical stressors (11). Typically, considerable psychological distress accompanies events (for example, stroke or traumatic brain injuries) that pro- mote increased cytokine concentrations in the brain. Likewise, IFN-α immunotherapy for cancer and hepatitis C is accompanied by the distress caused by illness, as well as that brought on by the treatment itself. Thus, it has been suggested that the affective effects of treatments or conditions that increase in- flammatory factors might be aggravated by stressful consequences that often stem from the treatments or the illness itself. Indeed, in rodents, proinflammatory treatments, in- cluding IFN-α, administered on a backdrop of stressors, such as social defeat or social disruption, exaggerated the increases in cor- ticosterone and brain monoamine utilization and mRNA expression of serotonin recep- tors, as well as diminishing the increase in peripheral and central transcripts for multiple cytokines elicited by the administration of a particular cytokine in the absence of addi- tional stress (8, 12). Likewise, in humans, self-reported signs of depression elicited by a stressor comprising social exclusion were increased after treatment with intravenous endotoxin (13). To explain how cytokine variations within the brain are translated into depres- sion, it was suggested that increases in cytokines, like that elicited by IFN-α im- munotherapy, lead to increased expression of the gene encoding tryptophan-degrad- ing enzyme indoleamine 2,3-dioxygenase (IDO), resulting in diminished 5-HT con- centration. Alternatively, depression might result from the conversion of tryptophan to kynurenine by IDO, which in turn produces the metabolites 3-hydroxy kynurenine and quinolinic acid, and the N-methyl-D-aspar- tate (NMDA) antagonist kynurenic acid. The neurotoxic actions of these metabolites might cause the development of depres- sion (14, 15). In this regard, the depression evident after stroke could be due to a cyto- kine-induced increase in IDO that leads to reduced 5-HT availability (16). The limited improvements that have been witnessed in response to treatments that fo- NEUROSCIENCE Inflammatory Factors Contribute to Depression and Its Comorbid Conditions Hymie Anisman* and Shawn Hayley *Corresponding author. Telephone: 613-520-2699; fax: 613-520-4095; e-mail: hymie_anisman@ carleton.ca Department of Neuroscience, Carleton Univer- sity, Ottawa, Ontario K1S 5B6, Canada. New perspectives have emerged regarding the processes associated with de- pressive disorders and their many comorbid conditions. Particular attention has been paid to the potential role of inflammatory factors in promoting these illness- es. These inflammatory responses include those elicited by pathogenic stimuli, as well as sterile inflammatory processes, such as those related to severe or chronic stress. These diverse challenges may activate common processes in which cytokines, which are inflammatory signaling molecules, provoke the dys- regulation of several growth factors, including brain-derived neurotrophic factor, fibroblast growth factor-2, macrophage migration inhibitory factor, and erythro- poietin. The result of such dysregulation favors the development of depressive disorders and their comorbid illnesses, such as heart disease, diabetes, auto- immune conditions, and poststroke depression. on January 1, 2017 http://stke.sciencemag.org/ Downloaded from