Anti-Inflammatory and Vasoprotective Activity of a Retroviral-Derived Peptide, Homologous to Human Endogenous Retroviruses: Endothelial Cell Effects

Abstract

Malignant and inflammatory tissues sometimes express endogenous retroviruses or their proteins. A highly-conserved sequence from retroviral transmembrane (TM) proteins, termed the “immunosuppressive domain (ID)”, is associated with inhibition of immune and inflammatory functions. An octadecapeptide (MN10021) from the ID of retroviral TM protein p15E inhibits in vitro release of pro-inflammatory cytokines and increases synthesis of anti-inflammatory IL-10. We sought to determine if MN10021 has significant in vivo effects. MN10021, prepared by solid-phase synthesis, was dimerized through a naturally-occurring, carboxy-terminal cysteine. In vivo anti-inflammatory activity was determined using a murine model of sodium periodate (NaIO4)-induced peritonitis. In vivo vasoprotective effects were determined using: (1) a carrageenan-induced model of disseminated intravascular coagulation (DIC) in mice; (2) a reverse passive Arthus model in guinea pigs; and (3) vasoregulatory effects in spontaneously hypertensive rats (SHR). In vitro studies included: (1) binding/uptake of MN10021 using human monocytes, cultured fibroblasts, and vascular endothelial cells (VEC); (2) gene expression by RT-PCR of MN10021-treated VEC; and (3) apoptosis of MN10021-treated VEC exposed to staurosporine or TNF-α. One-tenth nmol MN10021 inhibits 50 percent of the inflammatory response in the mouse peritonitis model. Furthermore, 73 nmol MN10021 completely protects mice in a lethal model of carrageenan-induced DIC and inhibits vascular leak in both the mouse DIC model and a guinea pig reverse passive Arthus reaction. MN10021 binds to and is taken up in a specific manner by both human monocytes and VEC but not by cultured human fibroblasts. Surprisingly, orally-administered MN10021 lowers blood pressure in SHR rats by 10–15% within 1 h suggesting a direct or indirect effect on the vascular endothelium. MN10021 and derived octapeptides induce iNOS (inducible nitric oxide synthase) mRNA in VEC and nitrate in VEC cell culture supernatants and protect VEC from induced apoptosis or necrosis. However, pretreatment of VEC with nitro-L-arginine methyl ester (L-NAME), while inhibiting the release of nitrate, does not block the anti-apoptotic effect of MN10021 and derived octapeptides suggesting that their potent vasoprotective and anti-inflammatory activity is not nitric oxide dependent.

Anti-inflammatory effect of a retrovirus-derived immunosuppressive peptide in mouse models

“…Together with the work of Cianciolo et al [27] our results indicate that virus-derived immunosuppressive peptides capable of down-regulating several proinflammatory cytokines such as TNF-α, IL-6, and IL-17C may represent a novel class of drugs for the treatment of excess inflammation.…”

Human Endogenous Retroviruses: Residues of Ancient Times Are Differentially Expressed in Crohn’s Disease

“…Both HERV groups are encoding for envelope proteins named HERV-FRD env (syncytin-2) and HERV-W env (syncytin-1) with a well-known immune modulatory function [17-20]. In our study, the HERV-FRD group, for example, is significantly less expressed in inflamed ileal CD and with the same tendency in inflamed colonic CD, corresponding with the respective expression data of syncytin-2.…”

“…They are also involved in osteoclast fusions in bone tissue and breast cancer-endothelial cell fusions [55, 56]. Furthermore, both proteins possess an ISD that modulates inflammatory processes [17-20]. Cianciolo et al [20] showed that an octadecapeptide derived from the ISD can inhibit pro-inflammatory cytokines and induces the expression of anti-inflammatory IL-10 in a murine model of peritonitis.…”

“…Furthermore, both proteins possess an ISD that modulates inflammatory processes [17-20]. Cianciolo et al [20] showed that an octadecapeptide derived from the ISD can inhibit pro-inflammatory cytokines and induces the expression of anti-inflammatory IL-10 in a murine model of peritonitis. Most recently, Tolstrup et al [19] performed a similar study, investigating the effects of a synthetic retroviral ISD peptide in 2 murine skin inflammation models.…”

“…Furthermore, HERV envelope proteins like syncytin-2 have a highly conserved region called the immunosuppressive domain (ISD), which seems to be important for materno-fetal immune tolerance at the fetal sited cell layer of the placenta [17]. Additionally, the ISD peptide has immunosuppressive properties on human peripheral blood mononuclear cells and, for example, in mouse models of skin or peritoneal inflammation [18-20]. A diminished expression of syncytins is related to preeclampsia [21].…”