Scientists at Singapore's Institute of Molecular and Cell Biology (IMCB), under the Agency for Science, Technology and Research (A*STAR), have identified the protein, WIP1, as the molecular "brake" that curbs severe inflammation in the body. The findings may prove relevant to developing more effective treatments against sepsis, the severe inflammatory condition caused by bacterial infection that afflicts many patients in intensive care units (ICU). In their paper, "WIP1 phosphatase is a negative regulator of NFκB signaling," published in the May 2009 issue of Nature Cell Biology (NCB), the IMCB scientists described their results showing the importance of WIP1 as an effective suppressor of inflammation and explained how the body was able to cope with an excess of inflammation brought on by the hyperactivation of the NFκB protein complex, a signaling molecule that plays a key role in triggering inflammation. "We have shown that WIP1 plays a critical role in suppressing the activity of NFκB and keeping NFκB levels within a safe range," said IMCB principal investigator Vinay Tergaonkar, Ph.D., who headed the research team. "In doing so, WIP1 minimizes the extent of inflammatory response that could lead to septic shock and subsequent death of patients." Dr. Tergaonkar and his colleagues compared the inflammatory response in mice lacking in WIP1 and in a control group of mice with normal WIP1 levels. The inflammatory response was higher in the WIP1 deficient animals. Correspondingly, the inflammatory response in mice with high WIP1 levels was suppressed.

Sepsis in humans frequently follows the body's attempt to thwart infectious agents such as bacteria, viruses and fungi. In many respects, the development of sepsis represents the harmful consequences of exuberant innate immune responses, resulting in high levels of proinflammatory mediators that are associated with organ failure, primarily in the heart, lungs, liver and kidneys. The early phases of sepsis are often associated with the onset of immunosuppression, which may compromise the body's ability to cope with infectious agents1. After the onset of sepsis, patients often develop 'septic shock', which is associated with a decrease in blood pressure, requiring the administration of vasopressors to maintain adequate blood pressure for organ perfusion. Such support may restore blood pressure, but does not address the cause, and it sometimes fails to adequately improve vascular perfusion of vital organs, including the brain. Very little is understood about the cause of falling cardiac output in septic shock, although cardiac failure of this type, referred to as septic cardiomyopathy, is considered to be reversible and does not seem to involve structural damage of the heart2. Several recent studies have provided insights into how the contractile power of the heart wanes during septic shock2. These studies have identified cardiosuppressive factors that are induced during sepsis and impair contractility of cardiomyocytes, the contractile cells of the heart. At least three types of factors adversely affect cardiomyocytes: bacterial lipopolysaccharide (LPS), the complement activation product C5a and certain cytokines (interleukin-1beta (IL-1beta), tumor necrosis factor-alpha (TNF-alpha) and IL-6). Blockade of these factors or their signaling pathways may be a promising therapeutic approach to treat complications of sepsis.

The immune response goes haywire during sepsis, a deadly condition triggered by infection. Richard S. Hotchkiss and his colleagues take the focus off of the prevailing view that the key aspect of this response is an exuberant inflammatory reaction. They assess recent human studies bolstering the notion that immunosuppression is also a major contributor to the disease. Many people with sepsis succumb to cardiac dysfunction, a process examined by Peter Ward. He showcases the factors that cause cardiomyocyte contractility to wane during the disease.