Regulation of inflammatory cytokines is a critical stage in inflammation, an important factor in autoimmune disease and cancer. Nitric oxide (NO) is known to be an important regulator of inflammatory cytokines, however, most existing studies focus on the role of NO synthesis in the regulation of inflammatory cytokines, and little is known about the role of NO metabolism. Since S-nitrosoglutathione reductase (GSNOR) is a key protein in the control of NO metabolism, investigating its role in inflammation will be important for understanding the role of NO metabolism. Here we found that GSNOR transcription and protein expression is downregulated by lipopolysaccharide (LPS) in RAW264.7 cells, an inflammatory cell model. Inhibitors of MEK1/2, p38 and PI3K significantly attenuate the decrease in GSNOR transcription. Furthermore, inhibition of the enzyme activity of GSNOR promoted expression of LPS-induced inflammatory cytokines IL-1β, IL-6 and TNF-α, whereas overexpression of GSNOR had the opposite effect. The anti-inflammatory drug trichostatin A (TSA) rescued the downregulation of GSNOR expression by LPS. Furthermore, inhibition of GSNOR impaired the anti-inflammatory effect of TSA by increasing the expression of IL-6 and TNF-α. In conclusion, our work reveals a new mechanism used by macrophage cells to enhance the inflammatory response by simultaneously upregulating inducible nitric oxide synthase(iNOS) and downregulating GSNOR, thus expanding our understanding of NO metabolism in inflammatory responses. This study shows that GSNOR is a novel regulator of inflammation and may be a potential target for the regulation of NO-mediated inflammation.