MKK3 mediates inflammatory response through modulation of mitochondrial function.

MKK3 mediates inflammatory response through modulation of mitochondrial function. Free Radic Biol Med. 2015 Feb 16; Authors: Srivastava A, Shinn AS, Lee PJ, Mannam P Abstract Mitochondria are increasingly recognized as drivers of inflammatory responses. MAP kinase kinase 3 (MKK3), a dual-specificity protein kinase, is activated in inflammation and in turn activates p38 MAP kinase signaling. Here we show that MKK3 influences mitochondrial function and acts as a critical mediator of inflammation. MKK3 deficient (MKK3(-/-)) mice and bone marrow derived macrophages (BMDMs) secreted less cytokines than wild type (WT) after LPS exposure. There was improved mitochondrial function, as measured by basal oxygen consumption rate, mitochondrial membrane potential, and ATP production, in MKK3(-/-) BMDMs. After LPS exposure, MKK3(-/-) BMDM did not show significant increase in cellular reactive oxygen species (ROS) production as well as mitochondrial superoxide (MitoSOX) compared to WT. Activation of two important inflammatory mediators i.e. the nuclear translocation of NF-κB and caspase-1 activity (a key component of the inflammasome), were lower in MKK3(-/-) BMDMs. p-38 and JNK activation were lower in MKK3(-/-) BMDMs compared to WT after exposure to LPS. Knockdown of MKK3 by siRNA in wild type BMDMs improved mitochondrial membrane potential, reduced LPS induced caspase-1 activation and attenuated cytokine secretion. Our studies establish MKK3 a...
Source: Free Radical Biology and Medicine - Category: Biology Authors: Tags: Free Radic Biol Med Source Type: research