Untitled

Abstract

We investigated the role of endogenous or exogenous nitric oxide (NO) on human lymphocyte function. We used sodium nitroprusside, nitroglycerine, S-nitroso-N-acetylpenicillamine, sodium nitrite and S-nitroso-L-glutathione as NO-generating compounds. All agents were used at doses that do not produce direct cytotoxicity as measured by trypan blue exclusion as well as chromium-51 release assay. The immune responses examined were peripheral blood lymphocytes (PBL) proliferation and IL-2 production after activation with OKT3 and PHA; allogeneic mediated proliferation and cell mediated cytotoxicity (CML) in MLR; IgG and IgM production after PBL activation with Con-A; proliferation and expression of IFN-gamma and IL-4 mRNA after activation of allogeneic CD4+T cell clones. Cytokine mRNA expression was measured by reverse transcriptase PCR. Our results show that proliferating lymphocytes do not produce a detectable amount of NO as measured by the Griess reaction. In separate experiments, the addition of NG-monomethyl-L-arginine (L-NMMA) did not affect lymphocyte proliferation. Sodium nitroprusside and nitroglycerine exerted a dose dependent antimitogenic effect, inhibited cytokine production and expression, CML generation and antibody production. DNA gel electrophoresis showed no evidence for enhanced programmed cell death. The antimitogenic effect could not be blocked by the NO scavengers, hemoglobin or methylene blue. In contrast, the other nitric oxide generating compounds did not inhibit lymphocyte mitogenesis. The results suggest that human lymphocytes do not produce appreciable amounts of NO to affect lymphocyte mitogenesis. Sodium nitroprusside and nitroglycerine have a potent but nonspecific immunoinhibitory effect on human lymphocyte function by a mechanism other than NO production. In addition, pharmacological levels of NO do not inhibit human lymphocyte mitogenesis.

Repurposing Drugs in Oncology (ReDO)—nitroglycerin as an anti-cancer agent

“…NO generated by iNOS is known to be involved in the regulation of lymphocyte populations, particularly T cell sub-types, and is also a key component of the lytic action of macrophages [ 59 – 61 ]. The action of exogenous NO on immune function is complex; for example there is some in vitro evidence for a non-specific immunosuppressive action for NTG [ 62 ], and in a rat model of atherosclerosis repeated exposure to NTG acted on macrophages to up-regulate matrix metalloproteinase-9 (MMP-9) and down-regulate tissue inhibitor of metalloproteinase-1 (TIMP-1) [ 63 ]. Additionally, there is evidence that NO is a key mediator in T-cell suppression by myeloid derived suppressor cells (MDSC) [ 64 , 65 ].…”