| “Every guest hates the others and the host hates them all”. From a physiological standpoint, this Albanian proverb bears truth for the immune system since its main objective is to seek out and destroy foreign pathogens. Innate immunity is the body's first mechanism to achieve this. Recognition of common patterns found on pathogens, such as components of bacterial cell walls or viral double-stranded RNA, allow the cell to undergo changes that increase the effectiveness of the innate immune response by inducing phagocytosis and the production of proinflammatory cytokines and chemokines.; Upon contact with virus or bacteria, cells induce the expression of type I interferons (IFNs) through the involvement and activation of interferon regulatory factor 3 (IRF3). The IFNs that are produced act in an autocrine and/or paracrine manner to induce the expression of proteins that have antiviral, antiproliferative, and immunomodulatory roles. Although the viral signaling pathway has been partly characterized, the pathway that leads from bacterial recognition at the cell surface to IRF3 activation has remained less scrutinized.; It has been previously shown that IRF3 activation by bacterial cell wall components, such as lipopolysaccharide (LPS), is a p38-dependent mechanism. In the present study, further investigation of this pathway revealed that reactive oxygen species (ROS) generated from LPS stimulation can activate the apoptosis signal-regulating kinase 1 (ASK1) which activate p38, leading to the induction of IRF3 dependent gene targets. Since ASK1 is an upstream activator of the mitogen activated protein kinase (MAPK) cascade, it was of interest to determine the intermediate kinase. Using anthrax lethal toxin, which cleaves the amino-terminus of the mitogen activated protein kinase kinase (MKK) family, it was shown that MKK6 has a role in the signaling pathway from LPS stimulation to IRF3 activation. Lastly, IRF3 activation was shown to have a role in sepsis, a syndrome characterized by an overactived immune response, and that inhibition of IRF3 activation by the hydroxy-stilbene piceatannol has a protective effect in a murine sepsis model. In conclusion, the data presented here provides evidence of the important role that IRF3 plays in the host response. |
