Cytokines in Endocrine Dysfunction of Plasma Cell Disorders

Figure 2

Overview of IL-6/soluble IL-6 receptor signaling at the nexus of endocrine function: illustrative examples. Binding of IL-6 to IL-6R and gp130 receptor complex leads to activation of Janus kinase- (JAK-) dependent pathways including mitogen-activated protein kinase (MAPK), protein kinase B (AKT)-phosphatidylinositol 3-kinase (PI3K), and signal transducer and activator of transcription 3 (STAT3). The IL-6 signaling mediated via a soluble IL-6 receptor (sIL-6R) leads to binding of IL-6/sIL-6R complex to gp130 triggering similar intracellular pathways (adapted from [30, 44, 45, 49]). In the states of NTI (nonthyroidal illness), an increase in rT3 production is a consequence of increased D3-mediated T3 (and T4) clearance through activation of the MAPK pathway [69]. Stress-induced HPA axis activation and GH-induced somatotroph adenoma growth are mediated via the STAT3 pathway [107]. In bovine chromaffin cells exposed to stress, IL-6 leads to activation of ERK 1/2 and STAT3 pathways and consequently to increased activity of tyrosine hydroxylase (TH), a rate-limiting enzyme in catecholamine synthesis, and to upregulation of downstream targets including secreted neuropeptides galanin, PTH-related peptide (PTHrP), G-protein-coupled receptor (GPR), stanniocalcin-1 (STC1), and hypoxia-inducible factor 1α (HIF-1α) [85]. The signaling via gp130 regulates the gonadal axis via activation of ERK and MAPK pathways on multiple levels: cycle regulation and proliferation of GnRH cells, impaired steroidogenesis, and increased permeability of blood-testis barrier (BTB) (through downregulation of occludin and delocalization of claudin 11 and tight junction protein 1 (TJP1)) [77, 115, 116]. Bone phenotype is illustrated through a rodent mutation model, where JAK/STAT and the SHP2/MAPK signaling regulate bone turnover and closure of the growth plate [56]. Soluble IL-6R seems to regulate osteoclast development in vitro; however, its relevance in vivo is unclear [92].