Novel Neurotrophin-1/B Cell-Stimulating Factor-3 (Cardiotrophin-Like Cytokine) Stimulates Corticotroph Function via a Signal Transducer and Activator of Transcription-Dependent Mechanism Negatively Regulated by Suppressor of Cytokine Signaling-3

Abstract

Novel neurotrophin-1/B cell-stimulating factor-3 (NNT-1/BSF-3) is a recently cloned gp130 cytokine, acting through the tripartite ciliary neurotrophic factor receptor (CNTFR) alpha/leukemia inhibitory factor receptor (LIFR)/gp130 receptor complex. The aim of the current study was to investigate the role of NNT-1/BSF-3 in corticotroph cell function and further characterize NNT-1/BSF-3 signaling pathways. Using RT-PCR, expression of ciliary neurotrophic factor receptor alpha, leukemia inhibitory factor receptor, and gp130 could be demonstrated in mRNA derived from murine corticotroph AtT-20 cells and murine pituitary tissue. Incubation of AtT-20 cells with 10 ng/ml recombinant human NNT-1/BSF-3 rapidly induced tyrosine-phosphorylation of signal transducer and activator of transcription (STAT)3 and STAT1 at 5 and 10 min. Proopiomelanocortin promoter activity and suppressor of cytokine signaling (SOCS)-3 promoter activity were significantly stimulated by NNT-1/BSF-3 4.0 +/- 0.3- and 5.9 +/- 0.2-fold, respectively. In comparison with untreated control, NNT-1/BSF-3 significantly stimulated ACTH secretion at 24 and 48 h 1.7 +/- 0.2-fold and 1.5 +/- 0.1-fold above baseline. In comparison with mock-transfected cells, stable overexpression of SOCS-3 in AtT-20 cells abolished NNT-1/BSF-3-induced STAT1 and STAT3 phosphorylation and almost completely inhibited STAT-dependent proopiomelanocortin promoter and SOCS-3 promoter activities. In addition, NNT-1/BSF-3-induced ACTH secretion at 48 h was significantly attenuated by SOCS-3 overexpression. In summary, we have shown that NNT-1/BSF-3 is a modulator of corticotroph cell function, which is negatively regulated by SOCS-3. Our data indicate that the activation of the Jak-STAT cascade is essential for corticotroph NNT-1/BSF-3 signaling. Further studies will have to investigate the possible in vivo role of NNT-1/BSF-3 as a neuroimmunoendocrine modulator of hypothalamus-pituitary-adrenal axis stress response.

Interleukin-31 mediates MAP kinase and STAT1/3 activation in intestinal epithelial cells and its expression is up-regulated in inflammatory bowel disease

“…36 Consistently, we demonstrated that SOCS3 can also inhibit signalling of other STAT activating cytokines. [37][38][39][40][41][42] IL31Ra belongs to the IL6 cytokine receptor (IL6R) family. IL6Rs have divergent effects on cell proliferation in different epithelial cell types.…”

Comparative Study of gp130 Cytokine Effects on Corticotroph AtT-20 Cells – Redundancy or Specificity of Neuroimmunoendocrine Modulators?

“…Also, the role of STAT-dependent suppressor of cytokine signaling (SOCS)-3 gene expression and its role as an endogenous negative regulator of cytokine-induced corticotroph function has been examined by experiments using LIF as a corticotroph stimulus [6]. Stimulatory effects on corticotroph cell function in vitro have also been described for human OSM (hOSM) [7][8][9][10][11], CNTF and NNT-1/BSF-3 [12], IL-6 [13][14][15][16] and IL-11 [17], respectively. However, as these effects have been investigated under various conditions, these studies cannot show the relative potency of each gp130 cytokine in corticotroph function.…”

Neuropoietin Attenuates Adipogenesis and Induces Insulin Resistance in Adipocytes

“…SOCS-3 proteins have been shown to play a role in both leptin resistance (40) and insulin resistance (41). Interestingly, SOCS-3 is induced by all known gp130 cytokines (32,33,(42)(43)(44)(45)(46)(47), as well as additional hormones, including insulin (48), growth hormone (49), and leptin (50). However, many inducers of SOCS-3, including CTNF, do not induce insulin resistance.…”