IRS activation not only involves specific immune (mentioned under 2.1. and 2.3.) and metabolic alterations (mentioned under 2.2. and 3), but also neuroendocrine changes such as hyperactivity of the HPA axis, and alterations in HP-thyroid (HPT) axis function and in the peripheral and central turnover of 5-HT.
4.1.1. Hypothalamic-Pituitary-Adrenal Axis. IL-1 and IL-6 exert potent enhancing effect on HPA-axis by stimulating hypothalamic corticotropin-releasing hormone (CRH), pituitary adrenocorticotropic hormone (ACTH), and adrenal steroidogenesis (Berkenbosch, Oers, & del Rey, 1987; Sapolsky, Rivier, & Yamamoto, 1987; Navarra, Tsagarakis, Faria, Rees, Besser, & Grossman, 1991). IL-6 may stimulate the HPA-axis at concentrations known to occur in human plasma (Navarra et al., 1991) and sufficiently to exert its actions on immune cells (Carmeliet, Vankelecom, Van Damme, Billiau, & Denef, 1991). It is reported that IL-l(3-induced ACTH, corticosterone, and IL-6 production is mediated by IL-1 type I receptors (Van Dam, Malinowsky, Lenc-zowski, Bartfai, & Tilders, 1998). It has been shown that HPA-axis hyperactivity during IRS activation is monokine-mediated and may result from monokine-induced serotonergic and catecholaminergic turnover (Dunn, 1988; Dunn, Powell, Meitin, & Small, 1989). Moreover, It is equally well established that some proinflammatory cytokines, such as IL-1, may induce resistance to the effects of glucocorticoid hormones, by influencing glucocorticoid receptor (GR) expression or GR translocation from the cytoplasm to the nucleus (Miller, Spencer, Pearce, Pisell, Tanapat, Leung, Dhabhar, McEwen, & Biron, 1997).
4.1.2. Hypothalamic-Pituitary-Thyroid Axis. A wide spectrum of alterations in HPT-axis function has been observed in patients with IRS activation or systemic non-thyroidal illnesses, caused by infection, sepsis, or injury (Kushner, 1982; Kaptein, 1986; Nicoloff & LoPresti, 1991). Abnormal low total T3 or T4, lowered basal TSH, and increased free T4 concentrations, may be observed in those conditions (Wartofsky & Burman, 1982; Wehmann, Gregerman, Burns, Saral, & Santos, 1985; Kaptein, 1986; Nicoloff & LoPresti, 1991; Hermus, Sweep, van der Meer, Ross, Smals, Benraad, & Kloppenborg, 1992). IL-ip and IL-6 are important mediators of the IRS-related alterations in HPT-axis function, e.g. IL-6 administration may suppress serum basal TSH (Dubuis, Dayer, Siegrist-Kaiser, & Burger, 1988; Fujii, Sato, Ozawa, Kasono, Imamura, Kanaji, Tsushima, & Shizume, 1989; Nicoloff & LoPresti, 1991; Hermus et al., 1992; Spath-Schwalbe, Hansen, Schmidt, Schrezenmeier, Marshall, Burger, Fehm, & Born, 1998).
4.1.3. Serotonin. Proinflammatory cytokines have profound effects on the peripheral and brain serotonergic systems. Peripherally and central administration of IL-lp, IFNy, and TNFa increase extracellular 5-HT concentrations in several brain areas such as the hypothalamus, the hippocampus, and the cortex (Clement, Buschmann, Rex, Grote, Opper, Gemsa, & Wesemann, 1997). IL-ip modulates the activity of the 5-HT transporter (Ramamoorthy, Ramamoorthy, Prasad, Bhat, Mahesh, Leibach, & Ganapathy, 1995), which plays a central role in serotonergic neurotransmi-sion by reuptake of 5-HT. Proinflammatory cytokines, such as IL-1 and IFNy may induce the activity of indoleamine-2,3-dioxygenase (IDO), the first enzyme of the kynurenine pathway, which converts tryptophan, the precursor of 5-HT, to kynurenic acid and quinolinic acid. Induction of IDO, which occurs in infection or inflammation, may be detrimental because it leads to depletion of the plasma concentrations of L-tryptophan and reduced synthesis of 5-HT in the brain (dependent partly of the plasma availability of tryptophan) with concomitant neurological effects like lowering of mood (Heyes, Saito, Crowley, Davis, Demitrack, Der, Dilling, Elia, Kruesi, Lackner, Larsen, Lee, Leonard, Markey, Martin, Milstein, Mouradian, Pranzatelli, Quearry, Salazar, Smith, Strauss, Sunderland, Swedo, & Tourtellotte, 1992). Plasma concentrations of tryptophan and the ratio of tryptophan to the sum of amino-acids known to compete for the same cerebral uptake mechanism (i.e. competing amino acids, CAA) are lower in major depressed patients than in normal volunteers (review: Maes & Meltzer, 1995). Brain 5-HT synthesis depends, in part, on the availability of plasma tryptophan, as indexed by total tryptophan plasma concentrations or the molar ratio of tryptophan to the grouped CAA (Maes & Meltzer, 1995).
4.2. Neuroendocrine Function, Cytokines, and Depression
Major depression is accompanied by HPA-axis hyperactivity, HPT-axis alterations, such as lower basal TSH concentrations, and serotonergic disturbances. The most consistently reported signs of HPA-axis hyperactivity in major depression are endogenous hypercortisolemia and the failure to suppress plasma Cortisol with the 1 mg DST (review: Maes et al., 1993a). The most consistent sign of HPT-axis dysfunction in depression is lower basal TSH (review: Maes et al., 1993a). There is converging evidence that disorders in peripheral and central serotonin (5-HT) activity are implicated in the pathophysiology of major depression (review: Maes & Meltzer, 1995): i) dysfunctions in the central presynaptic 5-HT neurons, which are, in part, related to a lowered avail ability of plasma L-tryptophan; and (adaptive?) changes in postsynaptic receptors such as increased number, affinity or responsivity of postsynaptic 5-HT2 receptors; and downregulated or desensitized postsynaptic 5-HT1A receptors. Therefore, we have hypothesized that, if major depression is indeed characterized by IRS activation, the glucocorticoid resistance in depression, lower serum basal TSH concentrations, and lower availability of tryptophan to the brain may be related to indicators of IRS activation. In accordance with this hypothesis we found the following, i) In depressed patients, there is a significant positive correlation between postdexamethasone Cortisol values and mitogen-stimulated IL-6 or IL-1 production, and a significant positive correlation between baseline plasma Cortisol and IL-6 concentrations (Maes et al., 1993a; 1993c). ii) In major depression, but not in normal controls, significant inverse relationships were found between serum basal TSH and plasma Hp concentrations (Maes, Scharpe, Cosyns, & Meltzer, 1994c). iii) Lower availability of plasma tryptophan to the brain was significantly correlated to serum IL-6, serum Hp, the a2 globulin fractions, neopterin and the CD4+/CD8+ T cell ratio (inversely), and to serum Alb, Fe,Tf, and Zn (all positively) (Maes et al., 1994c; Maes, Verkerk, Vandoolaeghe, Van Hunsel, Neels, Wauters, Demedts, & Scharpe, 1997e). Therefore, we have hypothesized that the most prominent neuroendocrine disorders in depression, i.e. HPA-axis hyperactivity, lower serum basal TSH, and lower tryptophan availability to the brain could be induced by IRS activation.
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