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J Clin Invest. 2011 May;121(5):1683-5. doi: 10.1172/JCI57748. Epub 2011 Apr 25.

Mitochondrial Ca²+ and ROS take center stage to orchestrate TNF-α-mediated inflammatory responses.

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  • 1Division of Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.


Proinflammatory stimuli induce inflammation that may progress to sepsis or chronic inflammatory disease. The cytokine TNF-α is an important endotoxin-induced inflammatory glycoprotein produced predominantly by macrophages and lymphocytes. TNF-α plays a major role in initiating signaling pathways and pathophysiological responses after engaging TNF receptors. In this issue of JCI, Rowlands et al. demonstrate that in lung microvessels, soluble TNF-α (sTNF-α) promotes the shedding of the TNF-α receptor 1 ectodomain via increased mitochondrial Ca²+ that leads to release of mitochondrial ROS. Shedding mediated by TNF-α-converting enzyme (TACE) results in an unattached TNF receptor, which participates in the scavenging of sTNF-α, thus limiting the propagation of the inflammatory response. These findings suggest that mitochondrial Ca²+, ROS, and TACE might be therapeutically targeted for treating pulmonary endothelial inflammation.

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