Human Recombinant Interleukin-1Beta and -Alpha, but Not Recombinant Tumor Necrosis Factor Alpha Stimulate ACTH Release from Rat Anterior Pituitary Cells in vitro in a Prostaglandin E₂ and cAMP Independent Manner

Abstract

The pituitary-adrenal axis is known to be stimulated during the acute-phase response. As cytokines play a central role in mediating the constellation of host response occurring during the acute-phase response it was of interest to assess the ability of cytokines to stimulate ACTH secretion from normal pituitary cells in culture. We used human recombinant interleukin-1β and -α (hrlL1β, hrlL1α) and human recombinant tumor necrosis factor α (hrTNFα) to analyze the ability of these cytokines to induce ACTH secretion from normal rat anterior pituitary cells in culture. We also investigated the possible roles of prostaglandin E₂ (PGE₂) and cAMP in the cellular transduction mechanism. After 3 days of incubation primary cultures of rat anterior pituitary cells were stimulated for 24 h with either hrlL1β, hrlL1α or hrTNFα alone or with the addition of dexamethasone or indomethacin. The culture media were analyzed for ACTH, PGE₂ and cAMP content. At doses ranging from 0.03 to 30 nM, hrlL1β stimulated the release of ACTH and PGE₂ in a dose-dependent manner. In contrast, at doses ranging from 3 to 60 nM, hrTNFα was unable to stimulate ACTH secretion although it stimulated PGE₂ synthesis. Time-course experiments demonstrated that hrlL1β (3 nM) stimulates ACTH production over a period of 8, 16 and 24 h, but not after a period of 4 h. In these experiments, hrlL1β failed to cause any change in the secretions of growth hormone and luteinizing hormone. In hrlL1β-stimulated cells, indomethacin (10 mM) completely inhibited PGE₂ production without significantly affecting ACTH release, whereas dexamethasone (50 nM), which also inhibited PGE₂ production, partially inhibited ACTH secretion. Finally indomethacin blocked the hrlL1β-induced cAMP accumulation obtained after 24 h, without significantly affecting hrlL1β-induced ACTH release. The results obtained with hrlL1α were similar to those obtained with hrlL1β. In conclusion, although hrlL1β, hrlL1α and hrTNFα stimulate PGE₂ synthesis, only hrlL1β and hrlL1α stimulate ACTH release from normal rat anterior pituitary cells in culture. The stimulation is partially inhibited by dexamethasone and the cellular transduction mechanism involved in this ACTH release does not depend on PGE₂ or cAMP. These results confirm the interaction between the endocrine and the immune systems. They suggest that the monokine-induced stimulation of the pituitary-adrenal axis may represent a potent negative feedback mechanism through which the immune system avoids an overshoot of the inflammatory and febrile effect stimulated during the acute-phase response.

Anatomical Localization of Corticotropin‐Releasing Factor and Arginine Vasopressin in the Human Hypothalamus; the Effect of Corticosteroids on their Concentrations in Human and Rat Hypothalami

“…This could also indicate that taken together, CRF,, and AVP account for all CRF, measured in our extracts, but definite evidence would require the comparison of this CRF, with that of standard solutions of CRF,, and AVP. Therefore, our results neither rule out the possibility that other known ACTH secretagogues such as Interleukin 1p (22,23), angiotensin 11 (24) and catecholamines (25) contribute to this biological activity, nor the fact that these other ACTH secretagogues may act in vivo within the hypothalamus to release CRF,, (26)(27)(28). To assess the effect of chronic administration of glucocorticoids on the levels of CRF,, and AVP we compared the hypothalamic contents of these two factors in patients who had received corticosteroids with those of control patients free of chronic corticosteroid administration.…”

The immune system as the sixth sense

“…Another group was pretreated by first injecting ahCRF earlier observation [84]. Beginning with the original demonstration of IL-1-induced ACTH release from a corticotroph cell line [3], AtT20, and subsequent confirmations and demonstrations of this response with primary pituitary cell cultures [85][86][87][88][89][90], a controversy ensued as to whether in vivo IL-1-mediated ACTH increases originated at the level of the hypothalamus or pituitary gland [91]. Although the consensus of studies concluded that ACTH release occurs as a result of IL-1 eliciting hypothalamic CRH release and that the CRH is entirely responsible for pituitary ACTH secretion [92][93][94][95], these findings were difficult to reconcile with the abundance of IL-1 receptors in the pituitary gland when compared with the hypothalamus [96,97].…”

Immunoneuroendocrine Connectivity: The Paradigm of the Thymus-Hypothalamus/Pituitary Axis

“…Growth hormone (GH), prolactin (PRL), luteinizing hormone (LH), and follicle-stimulating hormone (FSH) secretion by rat pituitary cells have been reported not to be influenced by IL-1· [9], whereas other reports have shown stimulation of GH, LH and thyroidstimulating hormone (TSH) secretion [10], together with inhibition of PRL release [11,12]. In rat pituitary cell cultures, ACTH secretion was stimulated [7,9,10,[12][13][14] or not influenced [15,16] by IL-1ß, whereas secretion of this pituitary hormone is enhanced by IL-1· in AtT20 cells [17][18][19][20] and in human corticotroph pituitary adenoma cell cultures [17]. Lastly, IL-1 further increases ACTH secretion by corticotrophs previously exposed to CRH [21].…”