Relationships between interleukin-6 activity, acute phase proteins, and function of the hypothalamic-pituitary-adrenal axis in severe depression

Maes, Michaël; Scharpé, Simon; Meltzer, Herbert Y.; Bosmans, Eugène; Suy, E.; Calabrese, Joseph R.; Cosyns, Paul

doi:10.1016/0165-1781(93)90027-e

Cited by 401 publications

(186 citation statements)

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“…SSRIs, such as sertraline and fluoxetine, attenuate the acute phase response in the olfactory bulbecomized and chronic mild stress model of depression in the rat Sluzewska et al 1994). Because an acute phase response in the above conditions is probably driven by hypersecretion of pro-inflammatory cytokines (Maes et al 1993b), these in vivo data are in accordance with the contention that antidepressants have negative immunoregulatory effects in vitro and in vivo. Not all studies, however, were able to find that short-term treatment with fluoxetine significantly suppressed initially increased serum IL-6 and IL-2R concentrations in major depression (Maes et al 1995a).…”

Section: Discussionsupporting

confidence: 73%

“…The evidence includes the following: (1) increased numbers of peripheral blood mononuclear cells (PBMC), such as neutrophils, monocytes, and activated T lymphocytes (Herbert and Cohen 1993;Maes et al 1992Maes et al , 1993cMuller et al 1993;Sluzewska et al 1996aSluzewska et al , 1996bSeidel et al 1996b;Perini et al 1995); (2) increased secretion of neopterin, a sensitive marker of cell-mediated immunity (Duch et al 1984;Dunbar et al 1992;Maes et al 1994;Bonaccorso et al 1997); (3) increased secretion of prostaglandin E2 (PGE2) in serum, CSF or culture supernatant obtained after polyclonal stimulation of whole blood (Linnoila et al 1983;Calabrese et al 1986;Song et al submitted;and (4) the presence of a moderate acute phase response, as indicated by increased serum concentrations of positive acute phase reactants, such as haptoglobin, C-reactive protein, and ␣ 1-antitrypsin (Maes et al 1993b(Maes et al , 1995b(Maes et al , 1997aJoyce et al 1992;Sluzewska et al 1996a) and decreased serum concentrations of negative acute phase reactants, such as albumin, transferrin, and zinc (Swartz 1990;Maes 1997;McLoughlin and Hodge 1990;Maes et al 1997b). Activation of the IRS has also been observed in the olfactory bulbectomized and the mild stress rat model of depression Sluzewska et al 1994).…”

mentioning

confidence: 99%

“…There is some evidence for increased (1) production of pro-inflammatory cytokines such as IL-1 ␤ , IL-6 and IFN ␥ in culture supernatant of mitogen-stimulated PBMC; and (2) serum concentrations of IL-6, IL-2, and IL-2 receptor in depression (Nassberger and TraskmanBendz 1993;Maes et al 1993aMaes et al , 1993bMaes et al , 1994Sluzewska et al 1995aSluzewska et al , 1995bSluzewska et al , 1996aSluzewska et al , 1996bSeidel et al 1995Seidel et al , 1996aFrommberger et al 1997). The above cytokines are known to orchestrate the key steps in the complex network, which regulates responses in cell-mediated and humoral immunity and in the IRS (Cavaillon 1996).…”

mentioning

confidence: 99%

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Negative Immunoregulatory Effects of Antidepressants Inhibition of Interferon-γ and Stimulation of Interleukin-10 Secretion

Maes¹,

Song

Lin

et al. 1999

Neuropsychopharmacology

339

179

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Section: Discussionsupporting

confidence: 73%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Negative Immunoregulatory Effects of Antidepressants Inhibition of Interferon-γ and Stimulation of Interleukin-10 Secretion

Maes¹,

Song

Lin

et al. 1999

Neuropsychopharmacology

339

179

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“…In particular, the group of Maes described an increase of the 'inflammatory response system ' and observed a relationship between proinflammatory immune markers, the severity of depression and measures of hypothalamus-pituitary-adrenal (HPA) axis hyperactivity. [78][79][80] As genetics play a role in MD, the genetics of the immune system in relation to MD has also been investigated. Certain cytokine gene polymorphisms, for example, in genes coding for IL-1 and TNF-a, may confer a greater susceptibility to develop MD.…”

Section: The Inflammatory Hypothesis Of Depressionmentioning

confidence: 99%

The immune-mediated alteration of serotonin and glutamate: towards an integrated view of depression

2007

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Beside the well-known deficiency in serotonergic neurotransmission as pathophysiological correlate of major depression (MD), recent evidence points to a pivotal role of increased glutamate receptor activation as well. However, cause and interaction of these neurotransmitter alterations are not understood. In this review, we present a hypothesis integrating current concepts of neurotransmission and hypothalamus-pituitary-adrenal (HPA) axis dysregulation with findings on immunological alterations and alterations in brain morphology in MD. An immune activation including increased production of proinflammatory cytokines has repeatedly been described in MD. Proinflammatory cytokines such as interleukin-2, interferon-c, or tumor necrosis factor-a activate the tryptophan-and serotonin-degrading enzyme indoleamine 2,3-dioxygenase (IDO). Depressive states during inflammatory somatic disorders are also associated with increased proinflammatory cytokines and increased consumption of tryptophan via activation of IDO. An enhanced consumption of serotonin and its precursor tryptophan through IDO activation could well explain the reduced availability of serotonergic neurotransmission in MD. An increased activation of IDO and its subsequent enzyme kynurenine monooxygenase by proinflammatory cytokines, moreover, leads to an enhanced production of quinolinic acid, a strong agonist of the glutamatergic N-methyl-D-aspartate receptor. In inflammatory states of the central nervous system, IDO is mainly activated in microglial cells, which preferentially metabolize tryptophan to the NMDA receptor agonist quinolinic acid, whereas astrocytes -counteracting this metabolism due to the lack of an enzyme of this metabolism -have been observed to be reduced in MD. Therefore the type 1/type 2 immune response imbalance, associated with an astrocyte/microglia imbalance, leads to serotonergic deficiency and glutamatergic overproduction. Astrocytes are further strongly involved in re-uptake and metabolic conversion of glutamate. The reduced number of astrocytes could contribute to both, a diminished counterregulation of IDO activity in microglia and an altered glutamatergic neurotransmission. Further search for antidepressant agents should take into account anti-inflammatory drugs, for example, cyclooxygenase-2 inhibitors, might exert antidepressant effects by acting on serotonergic deficiency, glutamatergic hyperfunction and antagonizing neurotoxic effects of quinolinic acid. Molecular Psychiatry (2007) 12, 988-1000; doi:10.1038/sj.mp.4002006; published online 24 April 2007 Keywords: major depression; psychoneuroimmunology; IDO; glutamate; immune system; serotonin Glutamate in depressionGlutamatergic neurotransmission is involved in depression and interacts with the serotonergic and noradrenergic systems The common therapeutic mechanism of antidepressant drugs is the enhancement of serotonergic and/or noradrenergic neurotransmission. On the basis of this pharmacological profile of antidepressant drugs, neurochemical research on major depression ...

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“…10 Increased PGE 2 in the saliva, the serum and the cerebrospinal fluid of depressed patients has previously been described. [11][12][13][14] According to the stimulating effect of PGE 2 on IL-6, most of the studies dealing with IL-6 report a marked increase of IL-6 in vitro production 15 or serum levels in depressed patients. 16,17 On the other hand, it was shown that tricyclic antidepressants and selective serotonin reuptake inhibitors attenuate the PGE 2 -synthesis, probably via inhibition of pro-inflammatory cytokines.…”

Section: Introductionmentioning

confidence: 99%

The cyclooxygenase-2 inhibitor celecoxib has therapeutic effects in major depression: results of a double-blind, randomized, placebo controlled, add-on pilot study to reboxetine

et al. 2006

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Signs of an inflammatory process, in particular increased pro-inflammatory cytokines and increased levels of prostaglandine E 2 (PGE 2 ), have repeatedly been described in major depression (MD). As cyclooxygenase-2 (COX-2) inhibitors inhibit the PGE 2 production and the production of pro-inflammatory cytokines, we performed a therapeutic trial with the COX-2 inhibitor celecoxib. In a prospective, double-blind, add-on study, 40 patients suffering from an acute depressive episode were randomly assigned to either reboxetine and celecoxib or to reboxetine plus placebo. After a wash-out period, 20 patients received 4-10 mg reboxetine plus placebo and 20 received reboxetine plus 400 mg celecoxib for 6 weeks. The treatment effect was calculated by analysis of variance. There were no significant differences between groups in age, sex, duration or severity of disease or psychopathology, or reboxetine dose or plasma levels. Over 6 weeks, both groups of patients showed significant improvement in scores of the Hamilton Depression Scale. However, the celecoxib group showed significantly greater improvement compared to the reboxetine-alone group. Additional treatment with celecoxib has significant positive effects on the therapeutic action of reboxetine with regard to depressive symptomatology. Moreover, the fact that treatment with an anti-inflammatory drug showed beneficial effects on MD indicates that inflammation is related to the pathomechanism of the disorder, although the exact mechanisms remain to become elucidated.

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Relationships between interleukin-6 activity, acute phase proteins, and function of the hypothalamic-pituitary-adrenal axis in severe depression

Cited by 401 publications

References 74 publications

Negative Immunoregulatory Effects of Antidepressants Inhibition of Interferon-γ and Stimulation of Interleukin-10 Secretion

Negative Immunoregulatory Effects of Antidepressants Inhibition of Interferon-γ and Stimulation of Interleukin-10 Secretion

The immune-mediated alteration of serotonin and glutamate: towards an integrated view of depression

The cyclooxygenase-2 inhibitor celecoxib has therapeutic effects in major depression: results of a double-blind, randomized, placebo controlled, add-on pilot study to reboxetine

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