Different endothelins stimulate cytokine production by peritoneal macrophages and microglial cell line

Abstract

Endothelins (ETs), potent vasoconstricting peptides, are produced by macrophages upon stimulation and may participate in the amplification or regulation of the inflammatory response. However, it is not clear whether ETs can act in an autocrine manner on macrophages and which role they play in relationship with other cytokines. To address these issues, we studied the effects of ETs on the production of inflammatory cytokines by mouse peritoneal macrophages or by a retrovirus-transformed microglial cell line. Here, we report that ET-2, but not ET-1 or ET-3, is able to stimulate the production of interleukin-1 (IL-1) and interleukin-6 (IL-6) by peptone-elicited mouse macrophages (pMO). In contrast, ET-3 and ET-1, but not ET-2, are active on microglial cells. No tumour necrosis factor-alpha (TNF-alpha) or nitric oxide (NO) were detected in the supernatants of ET-stimulated cultures. The activity of ET-2 on pMO was time and dose dependent and was inhibited by the addition of ETA and ETB receptor antagonists, BQ123 and IRL1038, respectively. In addition, when pMO were stimulated by interferon-gamma (IFN-gamma) in the presence of ET-2, a significant inhibition of IL-6 and IL-1 production was observed compared with the effects of the same doses of IFN-gamma or ET-2 used separately. The inhibition was specifically due to the activity of ET-2, since it was reversed by the addition of BQ123 or IRL1038. Similar results were seen when the content of NO in the supernatants of pMO stimulated by IFN-gamma plus ET-2 was evaluated. These results suggest that ETs may possess both a pro-inflammatory action on macrophages from different tissues and a regulatory activity on IFN-gamma.

Central endothelin ETBreceptors mediate IL-1-dependent fever induced by preformed pyrogenic factor and corticotropin-releasing factor in the rat

“…It also fits well with reports that CRF triggers the release of a preformed hypothalamic pool of IL-1␤ (34) and that IL-1 enhances central sympathetic outflow when given intracerebroventricularly (23) and causes fever when microinjected into the preoptic area (POA) (17). Furthermore, ET-1 stimulates IL-1 release from different cell types, including macrophages, microglia, and astrocytes (6,31). The increase in Fig.…”

Effect of anemonin on NO, ET-1 and ICAM-1 production in rat intestinal microvascular endothelial cells

“…ET-1 can in turn modulate the endothelial expression of adhesion molecules and cytokines production (McCarron et al, 1993;Speciale et al, 1998). Local administration of endothelin-1 induces mucosal ulcerations (LopezBelmonte and Whittle, 1994) and endothelin antagonism has been demonstrated to protect against mucosal ulceration induced by HCl and indomethacin.…”

Transient expression of endothelins in the amoeboid microglial cells in the developing rat brain

“…This suggests that ETs can also regulate amoeboid microglia through an autocrine manner in their synthesis and secretion of chemokines, MCP-1 and SDF-1. This view lends it support from the studies showing that ET-1 and ET-3 can stimulate microglial cells in the prodution of IL-1 and IL-6 (Speciale et al, 1998), and that monocyte chemoattractant protein-1 (MCP-1) production in macrophages is regulated by ETs (Chen et al, 2001). The specific localization of ETs in amoeboid microglia in this study has therefore greatly amplified the multiple functional roles of these peptides in the CNS, especially in the development stage.…”

“…Speciale et al (1998) had reported that different ETs stimulate cytokines production, such as IL-1 and IL-6 by mouse macrophages. The present RT-PCR study has shown that ET-1 mRNA coupled with that of MCP-1 and SDF-1 is markedly upregulated.…”