Cytokines and Their Role in Depression

Perspectives in Psychiatric Care, Oct 2008 by Wilson, Debra Rose, Warise, Lita

PURPOSE. This study aims to review the cytokines that mediate the inflammatory process, the interleukins and the interferons, and the interaction of cytokines with serotonin as causative factors in the role of depression.

CONCLUSIONS. Administration of proinflammatory cytokines to treat medical diseases induces depressive symptoms in humans. Patients diagnosed with depression tend to have high levels of cytokine activity and impaired immune response, as well as those patients suffering from inflammatory processes. Proinflammatory cytokines interfere with the body's feedback loop to reduce circulating corticosteroids during the stress response.

PRACTICE IMPLICATIONS. Serotonin levels, integrally associated with depression, are lowered when levels of circulating cytokines are high when the precursor tryptophan is reduced.

Search terms: Cytokines, depression, interferons, interleukins, serotonin

There is increasing evidence that depression is associated with alterations in immune functioning. Activation of the immune system during various medical conditions produces neural, neuroendocrine, and behavioral effects. The psychological and physiological effects of immune activation resemble many characteristics of depression. Recently, a number of studies examined whether there is a causative role of inflammatory mediators in the etiology of major depression. Cytokine immune therapy in humans suggests that proinflammatory cytokines induce depressive symptomology. Moreover, these depressive symptoms can be effectively reversed by antidepressant therapy (Kenis & Maes, 2002). For the purpose of this article, the focus will be placed on cytokines that mediate the inflammatory process, the interleukins and the interferons, and the interaction of cytokines with serotonin as causative factors in the role of depression.

Depression

The etiology of major depression is complex and incompletely understood. For some individuals, depression seems to descend "out of the blue"; otherwise healthy people-unexpectedly and without apparent cause-find themselves feeling profoundly depressed. For many others, depressive episodes are brought on by stressful life events, such as bereavement, loss of a job, or childbirth. Since depression does not occur in everyone, it would appear that some people are more vulnerable than others. Factors that may contribute to vulnerability include genetic heritage, a difficult childhood, and chronic low self-esteem (Lehne, 2007). Currently, there is strong evidence that depression involves alterations in multiple aspects of immunity that may contribute to the development or exacerbation of a number of medical disorders and also may play a role in the pathophysiology of depressive symptoms (Gold & Irwin, 2006).

Cytokines

Cytokines are low molecular weight regulatory proteins that are produced during all phases of an immune response. Cytokines are made primarily by and act predominantly on immune cells. These intercellular signaling molecules are very potent, act at very low concentrations, and usually regulate neighboring cells. Cytokines modulate reactions of the host to foreign antigens or injurious agents by regulating movement, proliferation, and differentiation of leukocytes and other cells. Cytokines are synthesized by many cell types but are made primarily by activated T lymphocytes and macrophages. The biologic properties of cytokines fall into several major functional groups. One group, the interleukins (IL-1, IL-6, tumor necrosis factor), mediate inflammation by producing fever and the acute-phase response by attracting and activating phagocytes (IL-8, IFN-γ). Other cytokines are maturation factors for the hematopoiesis of white or red blood cells. On the other hand, another group of cytokines, the interferons, are known for their triggering effect of depressive symptoms (Huether & McCance, 2008; Forth, 2005).

For inflammation to occur, many different kinds of cells must cooperate. That cooperation is achieved by the secretion of a variety of cytokine proteins that affect other cells. They can be either proinflammatory or antiinflammatory in nature, depending on whether they tend to induce or inhibit the inflammatory response. The binding of cytokines to a target cell often induces synthesis of additional cellular products (Huether & McCance, 2008).

Interleukins

Interleukins may be the most diverse and important chemical messengers in the immune system. Nearly 20 types of interleukins have been identified. Lymphocytes and macrophages are the primary sources of interleukins, but certain interleukins, such as IL-1, are also produced by endothelial cells, fibroblasts, and astrocytes. Interleukins have the following general functions: increasing T-cell sensitivity to antigens; stimulating B-cell activity, plasma cell formation, and antibody production; enhancing nonspecific defenses; and moderating the immune response (Martini, 2006). IL-1 is a proinflammatory cytokine produced mainly by macrophages. It is an endogenous pyrogen that reacts with receptors on cells of the hypothalamus and affects the body's thermostat, resulting in fever. IL-6 directly induces hepatocytes to produce many of the proteins needed in the inflammatory process. It also stimulates growth and differentiation of precursors of blood cells in the bone marrow and the growth of fibroblasts (Huether & McCance, 2008).