Cytokine Influences on the Nervous System

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The effects of cytokines and the presence of their receptors in the neuroendocrine system is currently the topic of much research. Of particular interest have been IL-1, IL-2, IL-6, and TNF-a, with particular emphasis on IL-1. A common pattern after immune activation is an increase in ACTH secretion and suppression of TSH release while the pattern for GH, PRL, and LH is less consistent (McCann et al. 1994).

The earliest report with IL-1 showed that it was able to stimulate the release of ACTH (Woloski et al. 1985). Several pathways appear to mediate the influence of IL-1 on neuroendocrine neurons and depend on the route of administration and on whether the cytokine acts at the level of the release and/or the biosynthesis of CRF (Rivest 1995). The increase in CRF mRNA appears to be dependent upon IL-1 in the CNS because central administration of the IL-1 receptor antagonist completely blocked the expression of CRF transcripts in the periventricular nucleus (Kakucska, Qi, Clark, and Lechan 1993). It has also been reported that IL-1 receptors can be demonstrated on the pituitary gland and that CRH can up-regulate IL-1 receptors on AtT-20 (Webster, Tracey, and DeSouza 1991). A finding by us has revealed that low levels of exogenous or endogenous CRH can sensitize the pituitary gland to the direct releasing activity of IL-1 (Payne, Weigent, and Blalock 1994). Therefore, one can conclude that IL-1 functions as a neuromodulator in the hypothalamus to enhance CRH release into the hypophyseal portal blood and that both IL-1 and CRH can sensitize the corticotroph, thus facilitating the release of ACTH.

The evidence suggests that both IL-1 and CRH activate corticotrophs, but they elicit different patterns in the regulation of POMC (Ruzicka and Huda 1995). Thus, IL-1 evoked an early release of P-lipotropin and an intermediate release of Pendorphin while CRH caused an early P-endorphin secretory response. Such a distinct pattern allows the pituitary to be specifically activated and therefore determine the interaction with the immune system. In addition to its effects on the hypothalamic-thyroid axis and the hypothalamic-gonadal axis. Thus, IL-1 inhibits the ovarian steroid-induced LH surge and release of hypothalamic luteinizing hormone releasing hormone (LHRH) in rats (Kalra, Sahu, and Kalra 1990). It also decreases plasma thyroid hormone and TSH levels in rats, probably by suppressing hypothalamic TRH secretion (Dubuis, Dayer, Siegrist-Kaiser, and Burger 1988).

IL-2 is the most potent regulator of pituitary ACTH secretion and is more active than the classical hypothalamic regulator, CRH (Karanth and McCann 1991). In rat pituitary cell cultures at low concentrations, IL-2 elevated ACTH, PRL, and TSH release and inhibited the release of follicle-stimulating hormone (FSH), luteinizing hormone (LH), and GH from hemipituitaries in vitro (Karanth and McCann 1991). It appears that both IL-2 and IL-6, in addition to their effects on hormone secretion, may participate in anterior pituitary cell growth regulation. Both cytokines were found to stimulate the growth of the GH3 cell line and inhibit the proliferation of normal rat anterior pituitary cells (Arzt, Stelzer, Renner, Lange, Muller, and Stalla 1992). It seems clear that some of the effects of IL-2 may occur directly at the level of the hypothalamus. Thus, IL-2 stimulates the release of GHRH from medial hypothalamic fragments and can stimulate the release of SOM (Karanth, Aguila, and McCann 1993). IL-2 given centrally induces a somewhat different pattern of response than the other cytokines because it stimulated instead of inhibited TSH release and also inhibited GH release, which was stimulated by low dosages of IL-1 and cachectin. As in the case of IL-1, IL-2 inhibited LH release but it also inhibited FSH release. Thus, this cytokine has powerful actions at the hypothalamic level to alter pituitary hormone release as well as act directly on the pituitary. The intracerebral ventricular injection of IL-6 results in an increase in plasma ACTH along with elevated temperature and a decrease in TSH (Spangelo and MacLeod

1990). Another group reported that IL-6 could stimulate the in vitro release of PRL, GH, and LH by dispersed pituitary cells (Bernton, Bryant, and Holaday 1987). The stimulation of PRL release by TRH could be enhanced by IL-6, indicating these hormones may have different intracellular mechanisms to stimulate hormone release (Spangelo, Judd, Isakson, and MacLeod 1989). The in vivo effect of IL-6 could be blocked by the prior administration of antibody against CRH, thus demonstrating that IL-6 stimulates ACTH secretion through the production of CRH (Naitoh et al. 1988).

IFN-y also has been shown to influence the secretory activity of anterior pituitary cells in culture. In vivo injection of IFN-y stimulated ACTH, with no effect on PRL and a delayed inhibition of GH and TSH release (Gonzalez, Riedel, Rettori, Yu, and McCann 1990). IFN-y at physiological concentrations has been shown to inhibit stimulated secretion of ACTH, PRL, and GH of pituitary cells cultured in vitro and stimulated with hypothalamic factors (Vankelecom et al. 1990). These results indicate that IFN-y may modulate GH secretion from the pituitary gland by both a direct suppressive effect at the level of the pituitary and indirect hypothalamic suppression involving stimulation of SOM release (Gonzalez, Aguila, and McCann

TNF-a is a cytokine produced by activated macrophages or monocytes that is important in the hormonal response to shock (Kelley, Arkins, and Li 1992). It has been shown that after only 1 h of incubation, TNF was capable of stimulating the release of ACTH, GH, TSH, and PRL from either overnight-cultured dispersed pituitary cells or hemipituitaries; however, the dose for these actions of TNF was 100-fold greater with dispersed cells than with hemipituitaries (Milenkovic, Rettori, Snyder, Reutler, and McCann 1989). In vivo, TNF-a has been reported to stimulate the release of ACTH, PRL, and GH similar to what has been observed with IL-1 (Bernardini et al. 1990). The stimulatory effect on ACTH release was completely inhibited by previous injection of CRH antiserum, suggesting that endogenous CRH serves as a mediator of the response.

In addition to these effects, TNF-a has been suggested to inhibit the hypothalamic-pituitary-thyroid axis at multiple levels (Dubuis et al. 1988) and the hypothalamic-pituitary-gonadal axis (Gaillard, Turnill, Sappino, and Muller 1990). Several recent studies also indicate that cytokines may synergize in the CNS. A form of motivation known as social investigation was used to demonstrate synergy between centrally injected (i.c.v.) IL-1 and TNF-a (Laye et al. 1995). IL-6 and its soluble receptor, when injected i.c.v., have been shown to interact in a way that potentiates fever and anorexia (Schobitz et al. 1995). Thus, the biological activity of cytokines may be dependent on the presence (or absence) of soluble receptors, which may exhibit either agonistic or antagonistic activity.

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