IGF-1 and IGFBP-3 in Inflammatory Cachexia

Abstract

Inflammation induces a wide response of the neuroendocrine system, which leads to modifications in all the endocrine axes. The hypothalamic-growth hormone (GH)-insulin-like growth factor-1 (IGF-1) axis is deeply affected by inflammation, its response being characterized by GH resistance and a decrease in circulating levels of IGF-1. The endocrine and metabolic responses to inflammation allow the organism to survive. However, in chronic inflammatory conditions, the inhibition of the hypothalamic-GH-IGF-1 axis contributes to the catabolic process, with skeletal muscle atrophy and cachexia. Here, we review the changes in pituitary GH secretion, IGF-1, and IGF-1 binding protein-3 (IGFBP-3), as well as the mechanism that mediated those responses. The contribution of GH and IGF-1 to muscle wasting during inflammation has also been analyzed.

Keywords: GH; IGF-1; IGFBP-3; cachexia; cytokines; glucocorticoids; inflammation; muscle wasting; nitric oxide; sepsis.

Figure 1

Effect of endotoxin or lipopolysaccharide (LPS) administration on the hypothalamic–GH–IGF-1 axis. At low dosage, LPS increased pituitary GH release, but with greater LPS dosages, an increase in hypothalamic somatostatin and a decrease in plasma GH is observed. Endotoxin directly decreased IGF-1 synthesis by hepatocytes through TLR4 activation, inducible nitric oxide synthase (iNOS) induction, and nitric oxide NO release. In addition, Kupffer cells, when stimulated by LPS, release inflammatory mediators (TNF-α, interleukins, and PGS), which further downregulate IGF-1 synthesis in hepatocytes. Whereas most IGF-1 is produced by hepatocytes, IGFBP-3 is mainly synthetized by Kupffer cells [49,50], and its synthesis is decreased by LPS. Red solid arrows indicate stimulatory (+) or inhibitory (−) effects of LPS. Black solid arrows indicate stimulatory and black dotted line indicates inhibitory effects of the hormones implicated in the GH-IGF-1 axis. Red border arrows indicate increased (upward) and decreased (downward) levels of the molecules/mediators in response to LPS.

Figure 2

Role of IGF-1 in inflammation-induced muscle atrophy. The decreased secretion of GH and/or GH resistance, together with the increased release of glucocorticoids (+) induce downregulation of plasma and muscle IGF-1 (−), and the increase in muscle IGFBP-3. Low plasma IGF-1 and high glucocorticoid levels increase atrogenes expression (MuRF-1 and atrogin-1), activate muscle proteolysis by the ubiquitin–proteasome system, and decrease protein synthesis. The increased IGFBP-3 expression together with the low IGF-1 levels in muscles decrease muscle proliferation. Thin arrows indicate stimulatory (+) and dotted ones inhibitory (−) effects of GC (green) and IGF-1 (blue) on muscle. Thick arrows indicate stimulation (green upward arrows) and inhibition (red downward arrows) of molecules/processes in muscle.