Jaks, STATs, Cytokines, and Sepsis.

Sepsis remains a significant cause of morbidity and mortality in the intensive care unit (68), affecting more than 500,000 patients per year in the United States (39). The incidence is increasing despite the major advances in the development of antimicrobial agents and other supportive treatments (56). Septic patients often succumb to a systemic inflammatory response, of which multiple organ failure is a main complication. There is no definitive treatment for multiple organ failure other than supportive treatment, such as assisted ventilation or renal dialysis. Research efforts now heavily focus on the mechanisms of multiple organ failure, with the hope that treatment options can be identified through a better understanding of these mechanisms. One current theory implicates an inappropriate cytokine response as the main protagonist in the development of multiple organ failure following an inflammatory stimulus (35, 48). Cytokines are low-molecular-weight polypeptides or glycoproteins that regulate numerous cellular functions and allow both autocrine and paracrine signaling. Cytokines regulate many of the pathways involved in the host inflammatory response to sepsis. They influence cell differentiation, proliferation, and activation and modulate proinflammatory and anti-inflammatory responses to allow the host to react appropriately to pathogens. The binding of a cytokine to a corresponding receptor initiates intracellular signal cascades, ultimately leading to changes in gene expression. These signals must rapidly transduce an extracellular signal to the nucleus. The Janus-kinase/ signal transducers and activators of transcription (Jak/STAT) pathway is employed in the signaling of many cytokines. Cytokine receptors do not, in general, have intrinsic tyrosine kinase activity and therefore require association with receptor-associated kinases in order to propagate a phosphorylation cascade. Jaks fulfill this function by their ability to associate with many of the cytokine receptors that are involved in regulatory pathways during a sepsis response. Cytokines bind to their receptors and cause receptor dimerization. This enables Jaks to phosphorylate each other as well as the cytokine receptors. Cytokine receptor phosphorylation allows binding of STATs via a specific binding domain. Once bound to the receptor, STATs are also phosphorylated by Jaks. STATs then dissociate from the receptors and dimerize. Dimerization enables translocation of STAT into the nucleus and binding to DNA in order to alter transcription (Fig. 1). Four Jaks and seven STATs have been identified to date in mammalian cells. Multiple Jaks and STATs, as well as the ability of STATs to homoor hetero-dimerize, allow for cytokine-specific cellular responses (47). This minireview describes a number of important cytokines involved in regulating the inflammatory response to sepsis, the importance of the Jak/STAT pathways, and how these pathways are regulated.