Inhibition of lactate dehydrogenase A suppresses inflammatory response in RAW 264.7 macrophages.

Lactate is an important metabolite in cellular metabolism and fluctuates in certain disease conditions including cancer and immune diseases. It was hypothesized that a decrease in lactate would modulate the inflammatory response elicited by lipopolysaccharides (LPS) in macrophages. When RAW 264.7 macrophages were treated with FX11, a specific lactate dehydrogenase (LDHA) inhibitor, the expression of the cytokines, inducible nitric oxide synthase (iNOS) and cyclooxygenase 2 (COX-2) was downregulated due to reduced cellular lactate levels. Genetic suppression of LDHA by small interfering RNA (siRNA) downregulated the LPS-activated expression of interleukin (IL)-6, iNOS, and COX-2, and reduced the production of IL-6 and nitrites. Pharmacological and genetic suppression of LDHA inhibited the phosphorylation of p38 mitogen-activated protein kinase. Microarray gene expression profile demonstrated that the genes involved in cell proliferation and inflammation were mainly altered by siRNA-mediated LDHA suppression. Collectively, the present observations suggest that lactate may be an important metabolite and implicated in regulation of inflammatory response.