scholarly journals Phosphorylation of Serine 68 in the IκB Kinase (IKK)-binding Domain of NEMO Interferes with the Structure of the IKK Complex and Tumor Necrosis Factor-α-induced NF-κB Activity

2007 ◽  
Vol 283 (1) ◽  
pp. 76-86 ◽  
Author(s):  
Lysann Palkowitsch ◽  
Julia Leidner ◽  
Sankar Ghosh ◽  
Ralf B. Marienfeld
Keyword(s):  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Tumor Necrosis Factor Α ◽  
Binding Domain ◽  
Iκb Kinase ◽  
Ikk Complex ◽  
Factor Α ◽  
Necrosis Factor

Adiponectin suppresses IκB kinase activation induced by tumor necrosis factor-α or high glucose in endothelial cells: role of cAMP and AMP kinase signaling

2007 ◽  
Vol 293 (6) ◽  
pp. E1836-E1844 ◽  
Author(s):  
Xiangdong Wu ◽  
Kalyankar Mahadev ◽  
Lauren Fuchsel ◽  
Raogo Ouedraogo ◽  
Shi-qiong Xu ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Tumor Necrosis Factor ◽  
High Glucose ◽  
Tumor Necrosis ◽  
Tumor Necrosis Factor Α ◽  
Amp Kinase ◽  
Inflammatory Signaling ◽  
Iκb Kinase ◽  
Factor Α ◽  
Necrosis Factor

Adiponectin is a protein secreted from adipocytes that exhibits salutary effects in the vascular endothelium by signaling mechanisms that are not well understood. In obesity-related disease states and type 2 diabetes, circulating substances, including tumor necrosis factor-α (TNFα) and high glucose, activate IκB kinase (IKK)β and reduce the abundance of its substrate, inhibitor of κB (IκB)α, leading to nuclear translocation of the transcription factor NF-κB and stimulation of an inflammatory signaling cascade closely associated with endothelial dysfunction. The present study demonstrates that the globular domain of adiponectin (gAd) potently suppresses the activation of IKKβ by either TNFα or high glucose in human umbilical vein endothelial cells and ameliorates the associated loss of IκBα protein. Interestingly, activation of AMP kinase was substantially more effective than cAMP signaling in suppressing high glucose-induced IKKβ activity, whereas both pathways were comparably active in suppressing the TNFα-induced increase in IKKβ. Both cAMP/protein kinase A signaling and activation of the AMP kinase pathway played a role in the suppression by gAd of TNFα- and high glucose-mediated IKKβ activation. These findings support an important role for adiponectin in anti-inflammatory signaling in the endothelium and also imply that multiple pathways are involved in the cellular effects of adiponectin.

scholarly journals Transient IκB Kinase Activity Mediates Temporal NF-κB Dynamics in Response to a Wide Range of Tumor Necrosis Factor-α Doses

2005 ◽  
Vol 281 (5) ◽  
pp. 2945-2950 ◽  
Author(s):  
Raymond Cheong ◽  
Adriel Bergmann ◽  
Shannon L. Werner ◽  
Joshua Regal ◽  
Alexander Hoffmann ◽  
...  
Keyword(s):  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Tumor Necrosis Factor Α ◽  
Kinase Activity ◽  
Iκb Kinase ◽  
Wide Range ◽  
Factor Α ◽  
Necrosis Factor

scholarly journals Free Cholesterol-loaded Macrophages Are an Abundant Source of Tumor Necrosis Factor-α and Interleukin-6

2005 ◽  
Vol 280 (23) ◽  
pp. 21763-21772 ◽  
Author(s):  
Yankun Li ◽  
Robert F. Schwabe ◽  
Tracie DeVries-Seimon ◽  
Pin Mei Yao ◽  
Marie-Christine Gerbod-Giannone ◽  
...  
Keyword(s):  
Tumor Necrosis Factor ◽  
Interleukin 6 ◽  
Free Cholesterol ◽  
Tumor Necrosis ◽  
Tumor Necrosis Factor Α ◽  
Vulnerable Plaques ◽  
Iκb Kinase ◽  
Tnf Α ◽  
Factor Α ◽  
Necrosis Factor

Two key features of atherosclerotic plaques that precipitate acute atherothrombotic vascular occlusion (“vulnerable plaques”) are abundant inflammatory mediators and macrophages with excess unesterified, or “free,” cholesterol (FC). Herein we show that FC accumulation in macrophages leads to the induction and secretion of two inflammatory cytokines, tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6). The increases in TNF-α and IL-6 mRNA and protein were mediated by FC-induced activation of the IκB kinase/NF-κB pathway as well as activation of MKK3/p38, Erk1/2, and JNK1/2 mitogen-activated protein kinases (MAPK). Activation of IκB kinase and JNK1/2 was needed for the induction of both cytokines. However, MKK3/p38 signaling was specifically involved in TNF-α induction, and Erk1/2 signaling was required for IL-6. Most interestingly, activation of all of the signaling pathways and induction of both cytokines required cholesterol trafficking to the endoplasmic reticulum (ER). The CHOP branch of the unfolded protein response, an ER stress pathway, was required for Erk1/2 activation and IL-6 induction. In contrast, one or more other ER-related pathways were responsible for activation of p38, JNK1/2, and IκB kinase/NF-κB and for the induction of TNF-α. These data suggest a novel scenario in which cytokines are induced in macrophages by endogenous cellular events triggered by excess ER cholesterol rather than by exogenous immune cell mediators. Moreover, this model may help explain the relationship between FC accumulation and inflammation in vulnerable plaques.

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