ATF3 confers resistance to pneumococcal infection through positive regulation of cytokine production

Abstract

Background. Activating transcription factor–3 (ATF3) is known as a suppressor of cytokine production after exposure to lipopolysaccharide or during gram-negative bacterial infection. However, the mechanism by which ATF3 regulates innate immunity against gram-positive bacterial infection, particularly Streptococcus pneumoniae, remains unknown. Methods. The wild-type and ATF3 knock-out (KO) mice were infected intranasally (i.n) or intraperitoneally with S. pneumoniae, and bacterial colonization or survival rate was determined. Pneumococcal pneumonia was in-duced by i.n infection, and ATF3 level was determined by Western blot. ATF3 KO cells or ATF3 siRNA transfection were used to determine expression of ATF3 downstream genes. Enzyme-linked immunosorbent assay was used to examine cytokines levels. Results. ATF3 was highly expressed in various cell lines in vitro and in many organs in vivo. Pneumolysin was a novel inducer of ATF3. Pneumococcal infection induced ATF3, which subsequently stimulated production of cyto-kines (tumor necrosis factor [TNF]–α, interleukin [IL]–1β, and interferon [IFN]–γ). ATF3-mediated cytokine in-duction protected the host from pneumococcal infection. In the pneumonia infection model, the bacterial clearance of wild-type mice was more efficient than those of ATF3 KO mice. Conclusions. Taken together, we can conclude that ATF3 regulates innate immunity positively upon pneumo-coccus infection by enhancing TNF-α, IL-1β, and IFN-γ expression and modulating bacterial clearance