Proinflammatory architecture of the host immune system

Analysis of molecular interaction networks of the host immune system indicates that it is fundamentally proinflammatory [58], and requires active control to reduce inflammatory reactions once started [59-61]. There are many positive feedback loops that escalate secretion of cytokines and promote further inflammation. Hyper-activation of a cytokine network, often called 'cytokine storm', is one of the major factors that aggravates patient health and may results in death. For example, influenza infection causes a range of cytokine release as its acute response [62, 63]. However, the infection is generally localized to epithelial cells yet extensive cytokine release often takes place systemically. This systemic release of cytokines particularly IL-1a and IFN-f aggravates inflammation leading to fever and lung inflammation, and sometimes leads to fatality. Mice infected with influenza virus in which IL-1a and IFN-f are suppressed show substantial mitigation of such risks [64, 65]. Similarly, infection with herpes simplex virus (HSV) triggers elevated production of IL-4 from CD4+ T cells and aggravates encephalitis [66]. The use of a certain types of drugs, such as vesarinone, for encephalomyocarditis (EMC) virus induced heart failure remarkably improved the survival rate of patients by reducing production of IL-1, IL-6, TNF-a, and IFN-f [67]. As vesarione is not an antiviral agent, it was concluded that the improvement in outcome heart failure reduction was due to suppression of TNF-a production that may be induced by lipopolysaccharide (LPS) stimulation [68]. Perhaps the most dramatic example of such cytokine overproduction is fulminant hepatitis where significant elevation of TNF-a and IL-1 has been reported [69].

A series of experimental and clinical observations naturally leads to the conclusion that control of cytokine production may effectively prevent escalation of infection-triggered organ dysfunctions, and more generally systemic inflammatory response syndrome (SIRS). While various mouse experiments confirmed mitigation of SIRS [70], clinical experiments reported so far have had mixed outcomes. System-level studies that involve individual variations of cytokine production and resulting dynamics may be warranted for proper development of cytokine modulation therapies.

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