Interleukin-1b Enhances Interleukin-1 Receptor Antagonist Content in Human Somatotroph Adenoma

In addition to the well-known modulation of immune and inflammatory responses, the interleukin-1 (IL-1) system has been shown to be involved in the regulation of anterior pituitary hormone secretion and growth. We previously demonstrated that IL-1 receptor antagonist (IL-1ra) is expressed in human pituitary adenomas cultured in vitro. In the present study, we investigated the regulation of IL-1ra protein by IL-1b (1–100 U/mL) in human somatotroph adenomas (n 5 9) cultured for 12–48 h. IL-1b significantly enhanced the concentration of IL-1ra dose dependently in the somatotroph adenoma cell lysates, whereas IL-1ra concentrations remained unchanged in the culture supernatants. Furthermore, basal IL-1ra concentrations were significantly higher in the cell lysates compared with the corresponding culture supernatants. The regulation of IL-1ra in somatotroph adenoma cells is different from human cultured monocytes, in which IL-1b significantly stimulated IL-1ra secretion into the culture supernatants, and no change of intracellular IL-1ra content was observed. Incubation of the somatotroph adenoma cells with 100 U/mL IL-1b did not result in a change of GH concentrations in the culture supernatants. Enhancement of intracellular IL-1ra protein by IL-1b may represent a mechanism intrinsic to somatotroph adenoma cells to counterregulate the response to IL-1b on hormone secretion or cellular growth. (J Clin Endocrinol Metab 83: 2429–2434, 1998) C have been demonstrated to be critically involved in neuroendocrine-immune interactions (reviewed in Refs. 1 and 2). The anterior pituitary gland not only represents a target but also a site of origin of cytokines. Among other cytokines, production of the inflammatory cytokine interleukin-1 (IL-1) was demonstrated in rat and mouse pituitary, increasing after treatment with bacterial lipopolysaccharide of the animals (3, 4). Furthermore, IL-1 receptors and messenger RNA (mRNA) were characterized in mouse and rat anterior pituitary cells as well as mouse AtT-20 corticotrophs (57). Because the predominant subpopulation of mouse anterior pituitary cells that express types I and II IL-1 receptors corresponds to GH-synthesizing cells (7), somatotrophs may be a preferential target for IL-1 actions within the pituitary. As for the human anterior pituitary, IL-1b expression was detected in pituitary adenomas (8) by RT-PCR of RNA. IL-6 synthesis, secretion, and immunoreactivity have been detected in human pituitary adenomas (9). Moreover, we have described IL-2 and IL-2 receptor expression by human corticotroph adenoma cells and murine AtT-20 corticotrophs (10) and also detected mRNA expression of the intracellular IL-1 receptor antagonist (IL1ra) by RT-PCR in human pituitary adenomas as well as IL-1ra colocalized with ACTH and GH immunoreactivity in corticotroph and somatotroph tumor cells, respectively (11). The IL-1ra constitutes a member of the IL-1 family that neutralizes the actions of IL-1 by binding to both types of IL-1 receptors during endotoxemia or inflammatory processes (reviewed in Ref. 12). Whereas the soluble form of IL-1ra is mainly expressed by activated monocytes and macrophages (reviewed in Ref. 12), the intracellular IL-1ra variant (13), is expressed in various tissues of epithelial or stromal origin (reviewed in Ref. 12). In addition, a second biologically active form of the intracellular IL-1ra containing an additional inframe 63-bp sequence has been characterized and referred to as intracellular IL-1ra type II (14). Several studies indicate that IL-1 and IL-1ra are differentially regulated (15–19) and IL-1 has been shown to stimulate soluble IL-1ra in monocytes and synovial fibroblasts (16, 20) as well as intracellular IL-1ra in human retinal pigment epithelial cells (21). IL-1 modulates hormone secretion at the level of hypothalamus, pituitary and peripheral glands (reviewed in Ref. 1). Concerning the effects of IL-1 on pituitary GH secretion however, both the in vitro and in vivo data are controversial and seem to depend on the experimental conditions used Received December 29, 1997. Revision received April 3, 1998. Accepted April 10, 1998. Address all correspondence and requests for reprints to: G. K. Stalla Max Planck Institute of Psychiatry, Department of Endocrinology, Kraepelinstrasse 10, D-80804 Munich, Germany. E-mail: stalla@ mpipsykl.mpg.de. * This work was supported by grants from the Deutsche Forschungsgemeinschaft (Sta 285/7–1) and the Commission of the European Communities (93.6014.AR/CI1-CT93–0092). 0021-972X/98/$03.00/0 Vol. 83, No. 7 Journal of Clinical Endocrinology and Metabolism Printed in U.S.A. Copyright © 1998 by The Endocrine Society