The regulatory role of nitric oxide in proinflammatory cytokine expression during the induction and resolution of inflammation

Nitric oxide is produced in various settings, including encounters with apoptotic cells, for regulation of cytokine expression, thereby contributing to inflammation. Upon inflammation, neutrophils and subsequently monocytes infiltrate into the involved site. Neutrophils perform functions such as bacterial killing or tissue destruction and then undergo apoptosis, whereas monocytes differentiate into macrophages at the site. Macrophages and other phagocytes finally clear apoptotic neutrophils, leading to resolution of the inflammation. One of the key steps during inflammation is leukocyte infiltration, which is controlled chiefly by chemokines for neutrophils and monocytes. The production of these chemokines is regulated positively or negatively by iNOS‐derived NO. Although the mechanisms underlying such dual effects of NO remain unknown, the level of NO and duration of NO exposure appear to be determining factors. The clearance of apoptotic neutrophils without causing further proinflammatory responses, on the other hand, is another key event during inflammation. The production of proinflammatory cytokines appears to be actively suppressed by TGF‐β and NO, which are produced by phagocytes upon interaction with apoptotic cells. Overall, NO plays a critical role during inflammation and therefore, remains a potential target for developing therapeutics for inflammatory diseases.