STAT5a/b contribute to sex bias in vascular disease: A neuroendocrine perspective

Previous studies have elucidated a neuroendocrine mechanism consisting of the hypothalamus (growth hormone releasing hormone, GHRH) – pituitary (growth hormone, GH) – STAT5a/b axis that underlies sex-biased gene expression in the liver. It is now established that male vs female patterned secretion of GHRH, and thus of circulating GH levels (“pulsatile” vs “more continuous” respectively), leading to differently patterned activation of PY-STAT5a/b in hepatocytes results in sex-biased gene expression of cohorts of hundreds of downstream genes. This review outlines new data in support of a STAT5a/b-based mechanism of sex bias in the vascular disease pulmonary hypertension (PH). Puzzling observations in PH include its 2-4-fold higher prevalence in women but a male-dominance in many rodent models, and, paradoxically, inhibition of PH development by estrogens in such models. We observed that conditional deletion of STAT5a/b in vascular smooth muscle cells (SMC) in mice converted the male-dominant model of chronic hypoxia-induced PH into a female-dominant phenotype. In human idiopathic PH, there was reduced STAT5a/b and PY-STAT5 in cells in late-stage obliterative pulmonary arterial lesions in both men and women. A juxtaposition of the prior liver data with the newer PH-related data drew attention to the hypothalamus-GH-STAT5 axis, which is the major target of estrogens at the level of the hypothalamus. This hypothesis explains many of the puzzling aspects of sex bias in PH in humans and rodent models. The extension of STAT5-anchored mechanisms of sex bias to vascular disease emphasizes the contribution of central neuroendocrine processes in generating sexual dimorphism in different tissues and cell types

Interleukin 6 in autoimmune and inflammatory diseases: a personal memoir

In this review, the author discusses the research that led to the identification and characterization of interleukin 6 (IL-6), including his own experience isolating IL-6, and the roles this cytokine has on autoimmune and inflammatory diseases. The cDNAs encoding B-cell stimulatory factor 2 (BSF-2), interferon (IFN)-β2 and a 26-kDa protein were independently cloned in 1986, which in turn led to the identification of each. To resolve the confusing nomenclature, these identical molecules were named IL-6. Characterization of IL-6 revealed a multifunctional cytokine that is involved in not only immune responses but also hematopoiesis, inflammation, and bone metabolism. Moreover, IL-6 makes significant contributions to such autoimmune and inflammatory diseases as rheumatoid arthritis (RA)

Interleukin 6 in autoimmune and inflammatory diseases: a personal memoir

In this review, the author discusses the research that led to the identification and characterization of interleukin 6 (IL-6), including his own experience isolating IL-6, and the roles this cytokine has on autoimmune and inflammatory diseases. The cDNAs encoding B-cell stimulatory factor 2 (BSF-2), interferon (IFN)-β2 and a 26-kDa protein were independently cloned in 1986, which in turn led to the identification of each. To resolve the confusing nomenclature, these identical molecules were named IL-6. Characterization of IL-6 revealed a multifunctional cytokine that is involved in not only immune responses but also hematopoiesis, inflammation, and bone metabolism. Moreover, IL-6 makes significant contributions to such autoimmune and inflammatory diseases as rheumatoid arthritis (RA)

Role of nitric oxide and prostaglandins in the potentiating effects of calcitonin gene-related peptide on lipopolysaccharide-induced interleukin-6 release from mouse peritoneal macrophages

Previous data from our laboratory have shown that calcitonin gene-related peptide (CGRP) has a potentiating effect on lipopolysaccharide-(LPS) induced interleukin-6 (IL-6) release from mouse macrophages. However, the mechanism of this effect was not clear. Since the nitric oxide (NO) and prostaglandins (PGs) induced by LPS might modulate IL-6 release, we examined whether NO and PGs were also involved in the potentiating effect of rat CGRP (rCGRP) on LPS-induced IL-6 release from mouse macrophages. The IL-6 level in the medium was measured by enzyme-linked immunosorbent assay. Accumulation of NO was assessed by measuring the presence of nitrite by the Greiss reaction. PGI2 was assessed by measuring the formation of 6-keto-prostaglandin F1α (6-keto-PGF1α) by radioimmunoassay. The results showed that the potentiating effect of rCGRP (0·1 nm) on LPS-induced IL-6 release was significantly inhibited by either 100 μm NG-monomethyl-l-arginine acetate (l-NMMA; an inhibitor of NO synthase) or 10 μm indomethacin (an inhibitor of cyclo-oxygenase). The LPS-induced NO and PGI2 production from these cells was increased significantly by rCGRP at 0·01–10 nm in a concentration-dependent manner, which was blocked by l-NMMA and indomethacin. These results suggest that rCGRP enhances the NO production elicited by LPS and subsequently increases the PGs production which is involved in the potentiating effect of rCGRP on LPS-induced IL-6 release from the peritoneal macrophages in the mouse