Retroviral-related peptides: not just for immunosuppression anymore
Department of Pathology, Duke University Medical Center, Durham, NC, United States
AIM: Human tumors produce antiinflammatory proteins related to the retroviral transmembrane (TM) protein p15E. These molecules were thought to confer a selective advantage to tumors by allowing them to escape immune surveillance. We have identified a 26-amino acid sequence in p15E (“the immunosuppressive domain”) that is highly conserved amongst all retroviral TM proteins, including human. MN10021, a peptide corresponding to the first 18 amino acids of this domain, inhibits the in vitro release of proinflammatory cytokines from human or murine leukocytes. We now sought to determine if MN10021 was antiinflammatory in vivo and what mechanism(s) might be involved. METHODS: MN10021 was tested in murine in vivo models of inflammation (peritonitis), disseminated intravascular coagulation (DIC;carrageenan-induced), and vascular leak. It was also tested in a rat hypertension model. MN10021 was then examined for its effects on human vascular endothelial (HUVEC) and smooth muscle cells (VSMC). In particular, we determined whether MN10021, or smaller analogs thereof, could upregulate the genes for inducible nitric oxide synthase (iNOS) and vascular endothelial growth factor (VEGF). RESULTS: MN10021, injected SC (doses ≥ 0.4 mcg), inhibits chemically-induced peritonitis in mice. At doses of ≥ 300 mcg, MN10021 protects mice against a lethal DIC reaction and inhibits vascular leak associated with DIC reactions in mice or reverse passive Arthus reactions in guinea pigs. Furthermore, MN10021 binds to HUVEC and, given orally (100 mg/kg), lowers blood pressure in SHR rats within 1 hr. Based on these results, we hypothesized that vascular endothelial cells (VEC) might represent the primary target of these antiinflammatory proteins and peptides. Nitric oxide (NO) has been shown to protect against apoptosis and to preserve the integrity of vascular endothelium and to protect against vascular leak in several animal models. We now report that MN10021 induces iNOS in both HUVEC and a vascular endothelial cell line (EA.hy926) as well as in VSMC. Furthermore, 8-amino acid peptides derived from MN10021 are also capable of inducing iNOS. In addition to iNOS, MN10021 and its smaller analogs also induce mRNA for both VEGF165 and VEGF189, two isoforms of the well-known pro-angiogenic growth factor. CONCLUSIONS: In summary, peptides derived from retroviral p15E, a protein which is antigenically related to antiinflammatory proteins associated with human neoplasms, induce both iNOS and VEGF. Release of these molecules might promote angiogenesis and, by virtue of their vasoprotective effects, inhibit inflammation. The release by malignant cells of such pro-angiogenic and antiinflammatory sequences might confer a survival advantage to such cells. We are investigating whether the presence of these sequences in tumors is associated with increased malignant or metastatic potential and whether antagonists to these sequences might have therapeutic utility.
Paper presented at the International Symposium on Predictive Oncology and Intervention Strategies; Nice, France; February 7 - 10, 2004; in plenary session 903 (Cancer immunity).