Pharmacologic IKK/NF-kappa;B inhibition causes antigen presenting cells to undergo TNFα dependent ROS-mediated programmed cell death

Jeremy S. Tilstra; Daniel F. Gaddy; Jing Zhao; Shaival H. Davé; Laura J. Niedernhofer; Scott E. Plevy; Paul D. Robbins

doi:10.1038/srep03631

Pharmacologic IKK/NF-kappa;B inhibition causes antigen presenting cells to undergo TNFα dependent ROS-mediated programmed cell death

Jeremy S. Tilstra
, Daniel F. Gaddy
, Jing Zhao
, Shaival H. Davé
, Laura J. Niedernhofer
, Scott E. Plevy
, Paul D. Robbins

Research output: Contribution to journal › Article › peer-review

24 Scopus citations

Abstract

Monocyte-derived antigen presenting cells (APC) are central mediators of the innate and adaptive immune response in inflammatory diseases. As such, APC are appropriate targets for therapeutic intervention to ameliorate certain diseases. APC differentiation, activation and functions are regulated by the NF-κB family of transcription factors. Herein, we examined the effect of NF-κB inhibition, via suppression of the IκB Kinase (IKK) complex, on APC function. Murine bone marrow-derived macrophages and dendritic cells (DC), as well as macrophage and DC lines, underwent rapid programmed cell death (PCD) after treatment with several IKK/NF-κB inhibitors through a TNFα-dependent mechanism. PCD was induced proximally by reactive oxygen species (ROS) formation, which causes a loss of mitochondrial membrane potential and activation of a caspase signaling cascade. NF-κB-inhibition-induced PCD of APC may be a key mechanism through which therapeutic targeting of NF-κB reduces inflammatory pathologies.

Original language	English (US)
Article number	3631
Journal	Scientific reports
Volume	4
DOIs	https://doi.org/10.1038/srep03631
State	Published - Jan 10 2014
Externally published	Yes

Bibliographical note

Funding Information:
This work was supported by National Institutes of Health Grants R01 DK54452, R41 DK074193 and P30 DK34987 to S.E.P., ES016114 to L.J.N., U01 NS058451, P30 AG024827, R01 CA103730, R01 AR051456, R21 AG033907 and DOD grants 17-03-1-0488 and 17-03-0142 to P.D.R., National Research Service Awards F30 ES013617 to S.H.D. and F30 AG032816 to J.S.T., a post-doctoral fellowship from the Juvenile Diabetes Research Foundation (JDRF) to D.F.G. and funding from the Broad Medical Research Program to S.E.P.

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SDG 3 Good Health and Well-being

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title = "Pharmacologic IKK/NF-kappa;B inhibition causes antigen presenting cells to undergo TNFα dependent ROS-mediated programmed cell death",

abstract = "Monocyte-derived antigen presenting cells (APC) are central mediators of the innate and adaptive immune response in inflammatory diseases. As such, APC are appropriate targets for therapeutic intervention to ameliorate certain diseases. APC differentiation, activation and functions are regulated by the NF-κB family of transcription factors. Herein, we examined the effect of NF-κB inhibition, via suppression of the IκB Kinase (IKK) complex, on APC function. Murine bone marrow-derived macrophages and dendritic cells (DC), as well as macrophage and DC lines, underwent rapid programmed cell death (PCD) after treatment with several IKK/NF-κB inhibitors through a TNFα-dependent mechanism. PCD was induced proximally by reactive oxygen species (ROS) formation, which causes a loss of mitochondrial membrane potential and activation of a caspase signaling cascade. NF-κB-inhibition-induced PCD of APC may be a key mechanism through which therapeutic targeting of NF-κB reduces inflammatory pathologies.",

author = "Tilstra, \{Jeremy S.\} and Gaddy, \{Daniel F.\} and Jing Zhao and Dav{\'e}, \{Shaival H.\} and Niedernhofer, \{Laura J.\} and Plevy, \{Scott E.\} and Robbins, \{Paul D.\}",

note = "Funding Information: This work was supported by National Institutes of Health Grants R01 DK54452, R41 DK074193 and P30 DK34987 to S.E.P., ES016114 to L.J.N., U01 NS058451, P30 AG024827, R01 CA103730, R01 AR051456, R21 AG033907 and DOD grants 17-03-1-0488 and 17-03-0142 to P.D.R., National Research Service Awards F30 ES013617 to S.H.D. and F30 AG032816 to J.S.T., a post-doctoral fellowship from the Juvenile Diabetes Research Foundation (JDRF) to D.F.G. and funding from the Broad Medical Research Program to S.E.P.",

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AU - Zhao, Jing

AU - Davé, Shaival H.

AU - Niedernhofer, Laura J.

AU - Plevy, Scott E.

AU - Robbins, Paul D.

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N2 - Monocyte-derived antigen presenting cells (APC) are central mediators of the innate and adaptive immune response in inflammatory diseases. As such, APC are appropriate targets for therapeutic intervention to ameliorate certain diseases. APC differentiation, activation and functions are regulated by the NF-κB family of transcription factors. Herein, we examined the effect of NF-κB inhibition, via suppression of the IκB Kinase (IKK) complex, on APC function. Murine bone marrow-derived macrophages and dendritic cells (DC), as well as macrophage and DC lines, underwent rapid programmed cell death (PCD) after treatment with several IKK/NF-κB inhibitors through a TNFα-dependent mechanism. PCD was induced proximally by reactive oxygen species (ROS) formation, which causes a loss of mitochondrial membrane potential and activation of a caspase signaling cascade. NF-κB-inhibition-induced PCD of APC may be a key mechanism through which therapeutic targeting of NF-κB reduces inflammatory pathologies.

AB - Monocyte-derived antigen presenting cells (APC) are central mediators of the innate and adaptive immune response in inflammatory diseases. As such, APC are appropriate targets for therapeutic intervention to ameliorate certain diseases. APC differentiation, activation and functions are regulated by the NF-κB family of transcription factors. Herein, we examined the effect of NF-κB inhibition, via suppression of the IκB Kinase (IKK) complex, on APC function. Murine bone marrow-derived macrophages and dendritic cells (DC), as well as macrophage and DC lines, underwent rapid programmed cell death (PCD) after treatment with several IKK/NF-κB inhibitors through a TNFα-dependent mechanism. PCD was induced proximally by reactive oxygen species (ROS) formation, which causes a loss of mitochondrial membrane potential and activation of a caspase signaling cascade. NF-κB-inhibition-induced PCD of APC may be a key mechanism through which therapeutic targeting of NF-κB reduces inflammatory pathologies.

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Pharmacologic IKK/NF-kappa;B inhibition causes antigen presenting cells to undergo TNFα dependent ROS-mediated programmed cell death

Abstract

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