Christoph J. Auernhammer

The central role of SOCS-3 in integrating the neuro-immunoendocrine interface

Cytokines and related signaling molecules lead to profound regulatory changes in differentiated cell function, modulating immune functions, the stress response, energy metabolism, growth, and reproduction. A network of intracellular molecules that dampen or inhibit the effects of these pleiotropic factors provides a crucial counterbalance to cytokine signals. Recent studies have shown that negative feedback, initiated in the various target tissues by the cytokines themselves, is central to endocrine homeostasis. Cytokine-mediated adrenocorticotropin hormone (ACTH) and cortisol overproduction, for instance, is prevented by tightly regulated cytokine-induced intracellular negative control systems. Likewise, growth hormone (GH) signaling is abrogated by cytokine-induced proteins, providing an explanation for GH resistance and stunted growth observed in states of elevated cytokine activity, including inflammation, starvation, and chronic illness. This article explores the role of the signal suppressor SOCS-3 in inhibiting the actions of neuro-endocrine cytokines and hormones, while maintaining the plasticity of the ultimate neuro-immune endocrine responses.

Leukemia Inhibitory Factor Modulates Interleukin-1β-Induced Activation of the Hypothalamo-Pituitary-Adrenal Axis1

We have shown that leukemia inhibitory factor (LIF) is expressed in corticotroph cells and stimulates POMC gene expression and ACTH secretion in vivo and in vitro. We therefore examined the regulation of in vitro and in vivo pituitary LIF expression by cytokines known to stimulate the hypothalamo-pituitary-adrenal axis. In the corticotroph cell line AtT-20/D16v-F2, recombinant murine interleukin-1β (IL-1β; 0.1–10.0 ng/ml) caused a 5- to 10-fold increase in LIF messenger RNA (mRNA) levels. LIF mRNA expression was induced as early as 1 h, peaked at 2 h, and still persistently elevated above the baseline after 8 h. This effect of IL-1β on LIF mRNA expression was abolished by preincubation with human IL-1 receptor antagonist (100 ng/ml) or antimurine IL-1β antibody (10 μg/ml). Tumor necrosis factor-α (20 ng/ml) only modestly increased LIF mRNA, but was synergistic with IL-1β (up to 2.5-fold). In contrast, IL-2 and IL-6 did not alter LIF mRNA. In C57BL/6 mice, ip injection of 100 ng IL-1β increased plasma ACTH...

SOCS proteins: modulators of neuroimmunoendocrine functions. Impact on corticotroph LIF signaling.

Abstract: Several members of the newly characterized family of suppressor of cytokine signaling (SOCS) proteins‐such as SOCS‐1, SOCS‐3, and CIS‐act as negative regulators of the cytokine‐induced Jak‐STAT signaling cascade. The expression of SOCS proteins is stimulated by a variety of cytokines and hormones in a tissue‐specific manner. This article reviews our current understanding of SOCS proteins and their role as modulators of neuroimmunoendocrine functions, for example, in signaling of leptin, growth hormone, and prolactin, specially focusing on the impact of SOCS proteins on corticotroph leukemia inhibitory factor (LIF) signaling. LIF, a member of the gp130 sharing cytokine family, modulates pituitary development, POMC gene expression, and ACTH secretion. Current data on the negative autoregulatory function of the suppressor of cytokine signaling, SOCS‐3, in LIF‐induced POMC gene expression and ACTH secretion are extensively discussed.

gp130-Related Cytokines

Cytokines are secreted multifunctional proteins, exerting local autocrine and paracrine, as well as sys- temic endocrine actions. Although originally thought to be derived from hematopoietic and immune cells, these molecules are secreted by a variety of different cell types and affect multiple target cells. Cytokine actions are characterized by biological pleiotropy and redundancy. Most cytokines affect different biological target cells and act in a cell type specific fashion. Cytokine families often exhibit similar or overlapping functions in a specific target tissue, as they use common receptor subunits and signaling cascades. Different factors, for example, interleukins (ILs), tumor necrosis factors, interferons (IFNs), colony-stimulating factors, chemokines, and others, have been categorized as cytokines, and the definition criteria are some what arbitrary. Cytokines act through specific receptors and use common signaling pathways.