Synergistic Effects of Interleukin-1β, Interleukin-6, and Tumor Necrosis Factor-α Central Monoamine, Corticosterone, and Behavioral Variations

Abstract

The proinflammatory cytokines interleukin-1 ␤ (IL-1 ␤ ), IL-6, and tumor necrosis factor-alpha (TNF-␣ Dopamine; Monoamines; Neurochemical; Norepinephrine; Serotonin; Synergism; It is clear that interactions occur between the immune, endocrine, central, and autonomic nervous systems. Immunological manipulations (or products of an activated immune system, e.g., cytokines) may affect neuroendocrine and central neurotransmitter processes, and conversely, neuroendocrine and central neurotransmitter alterations may impact on immune activity (Blalock 1994;Dunn 1990;Rivier 1993;Rothwell et al. 1997). It has been posited that, among other things, the immune system acts like a sensory organ informing the brain of antigenic challenge (Blalock 1994) and that immune activation may be interpreted by the CNS as a stressor Dunn 1990). Further, cytokines may be part of a regulatory loop that, by virtue of effects on CNS functioning, might influence behavioral outputs and may even contribute to the symptoms of behavioral pathologies, including mood and anxietyrelated disorders . Indeed, in humans, depression was associated with variations of plasma cytokines, including interleukin-1 ␤ (IL-1 ␤ ), IL-1 receptor antagonist (IL-1Ra), IL-2, soluble IL-2 receptors, IL-6, and soluble IL-6 receptors Maes 1995;Maes et al. 1995;Muller and Ackenheil 1998).From the Institute of Neuroscience, Carleton University, Ottawa, Ontario, Canada (KB, SH, RZ, HA); and School of Psychology and Department of Cellular and Molecular Medicine (ZM), University of Ottawa, Ottawa, Ontario, Canada.Address correspondence to: Hymie Anisman, Ph.D., Life Sciences Research Building, Carleton University. Ottawa, Ontario K1S 5B6, Canada.Received January 28, 1999; revised May 10, 1999; accepted December 6, 1999. N EUROPSYCHOPHARMACOLOGY 2000 -VOL . 22 , NO . 6 Synergistic Effects of Cytokines 567Cytokines and bacterial endotoxins, such as lipopolysaccharide (LPS), induce a constellation of apparently adaptive behavioral changes, collectively referred to as "sickness behaviors" . For instance, these agents induce fever, reduce social exploration, sexual behaviors, and food consumption (Bluthe et al. 1992;Johnson et al. 1996;Plata-Salaman 1988;Plata-Salaman et al. 1988;O'Reilly et al. 1987). In addition, endotoxins may induce anxiogenic-like effects ) and disrupt responding for rewarding brain stimulation (Borowski et al. 1998), possibly reflecting anhedonic effects elicited by the immune challenge. The behavioral effects of endotoxin and cytokine treatment are paralleled by increased hypothalamic-pituitary-adrenal (HPA) activity, as reflected by increased activity of corticotropin releasing hormone (CRH) and elevated plasma ACTH and corticosterone levels (Kakucksa et al. 1993;Tilders et al. 1993). Inasmuch as cytokines elicit several effects similar to those of LPS, it has been assumed that at least some of the endotoxin effects involve IL-1 ␤ , or this cytokine acting conjointly or synergistically with IL-6 and/or TNF-␣ (Dunn 1992a; Ebisui et al. 1994;Long et...

Clinical outcomes, quality of life, and diagnostic uncertainty in the first year of polymyalgia rheumatica

“…The relationship we observed between elevated acute-phase markers of ESR or CRP level and poorer mental QOL is surprising, given that the acute-phase markers showed a stronger relationship than duration of morning stiffness, and that neither ESR nor CRP level showed a strong association with physical QOL. The impaired mental QOL and depression commonly seen in patients with PMR may therefore be related to the neurologic effects of circulating cytokines such as interleukin-6, which is elevated in PMR and may have significant effects on the central nervous system (30,31).…”

Central blockade of melanocortin receptors attenuates the metabolic and locomotor responses to peripheral interleukin-1β administration

“…This may be partially explained by the expression of IL-1 receptor (Ericsson et al, 1995) and the absence of the TNF receptors (p55 and p75 (Nadeau and Rivest, 1999)) in the arcuate nucleus. Whether higher doses of TNF-α would have resulted in additional effects on the recorded metabolic parameters is yet to be determined, and may be supported by the data showing that the effective dose to lower consumption of a palatable liquid was 10-fold greater for TNF-α compared to IL-1β (Brebner et al, 2000). That being said, we intentionally chose doses of IL-1β and TNF-α that resulted in comparable levels of anorexia and comparable levels of neuronal activation in the PVH ( See Fig 1), a brain region critical for the regulation of appetite and metabolism (Sawchenko, 1998).…”

Role of inflammatory cytokines in depression: Focus on interleukin-1β

“…Serum levels of IL-6 and tumor necrosis factor (TNF) have been reported to be higher in depressed subjects when compared with non-depressed subjects (20). Furthermore, it has been stated that the three pro-inflammatory cytokines, IL-6, TNF and IL-1β are implicated in the pathophysiology of depressive illness (21). IL-6 has been proposed to be central in the systemic consequences of psychological stress, mediating with stress through the hypothalamic-pituitary-adrenal (HPA) axis and catecholamines leading to insulin resistance, coagulation abnormalities and endothelial dysfunction (22)(23)(24).…”