Abstract
This study was designed to investigate the relationship between NO, IL-12, and TNF-α production by J774A.1 macrophages activated with LPS and IFN-γ in the presence of N-[3-(aminomethyl)benzyl]acetamidine (1400 W). 1400 W is a novel, highly selective inhibitor of inducible nitric oxide synthase (iNOS). We compared the obtained data with the effect of NG-monomethyl-L-arginine (L-NMMA) (a nonselective NOS inhibitor) and L-NG-(1-iminoethyl)lysine (L-NIL) (a relatively selective inhibitor of iNOS activity) on cells in this model. To investigate the involvement of an exogenous NO on IL-12 and TNF-α production we used NO donor—S-nitrosocaptopril (S-NO-Cap). The most potent inhibitor of NO generation was 1400 W. This compound also markedly increased IL-12 p40 secretion and decreased TNF-α release. L-NIL suppressed both NO and TNF-α production, but it did not change IL-12 p40 synthesis. The effect of L-NMMA on NO generation was weaker than other inhibitors. Moreover, it decreased TNF-α secretion slightly but not significantly. IL-12 p40 production by stimulated cells was inhibited by S-NO-Cap in a dose dependent manner, but no effect on TNF-α release was observed. The potency and selectivity of 1400 W as an inhibitor of iNOS and cytokine release modifier are encouraging for therapeutic use.
Highlights
Cytokines are low molecular weight polypeptides that initiate the inflammatory response and define the magnitude and the nature of the acquired immune response
Interleukin 12 (IL-12) induces commitment from the T helper 0 (Th0) to Th1 phenotype [3, 4]
The nitrite, IL-12 p40, and TNF-α levels were determined after 18 h of stimulation with LPS (100 ng/mL) and IFN-γ (25 U/mL) in the presence or absence of inducible nitric oxide synthase (iNOS) inhibitors
Summary
Cytokines are low molecular weight polypeptides that initiate the inflammatory response and define the magnitude and the nature of the acquired immune response. Interleukin 12 (IL-12), tumor necrosis factor alpha (TNF-α), and interferon gamma (IFN-γ) are three inflammatory mediators, which have significant impact on the cytokine balance and type of immune response. Nitric oxide (NO) seems to participate in this regulation [1, 2]. IL-12 (a heterodimer composed of two subunits: p35 and p40) induces commitment from the T helper 0 (Th0) to Th1 phenotype [3, 4]. NO has been suggested to inhibit IL-12 transcription and to act as negative feedback on Th1 cell development [5]. TNF-α seems to be a specific inhibitor of IL-12 p40 secretion from human macrophages [6]
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