IκBα and IκBβ possess injury context-specific functions that uniquely influence hepatic NF-κB induction and inflammation

Fan, Chenguang; Li, Qiang; Zhang, Yulong; Liu, Xiaoming; Luo, Meihui; Abbott, Duane; Zhou, Weihong; Engelhardt, John F.

doi:10.1172/jci17337

Cited by 71 publications

(26 citation statements)

References 50 publications

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“…Recent studies have implicated a key role for Src in NF-B activation by oxidant stress and inflammatory signals. Src activated NF-B by both IB kinase-dependent and -independent mechanisms (53)(54)(55). Further studies are required to verify the specific mechanisms by which Src regulates RAGE-induced NF-B activation.…”

Section: Discussionmentioning

confidence: 99%

Key Role of Src Kinase in S100B-induced Activation of the Receptor for Advanced Glycation End Products in Vascular Smooth Muscle Cells

Reddy

Sahar

et al. 2006

Journal of Biological Chemistry

140

121

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The receptor for advanced glycation end products (RAGE) and its ligands have been implicated in the activation of oxidant stress and inflammatory pathways in vascular smooth muscle cells (VSMCs) leading to the initiation and augmentation of atherosclerosis. Here we report that non-receptor Src tyrosine kinase and the membrane protein caveolin-1 (Cav-1) play a key role in the activation of RAGE by S100B in VSMCs. S100B increased the activation of Src kinase and tyrosine phosphorylation of caveolin-1 in VSMCs. A RAGEspecific antibody blocked both these effects. An inhibitor of Src kinase, PP2, significantly blocked S100B-induced activation of Src kinase, mitogen-activated protein kinases, transcription factors NF-B and STAT3, superoxide production, tyrosine phosphorylation of Cav-1, VSMC migration, and expression of the pro-inflammatory genes monocyte chemotactic protein-1 and interleukin-6. Cholesterol depletion also inhibited S100B-induced effects indicating the requirement for intact caveolae in RAGE-specific signaling. Nucleofection of either a Src dominant negative mutant, or a Cav-1 mutant lacking the scaffolding domain, or Cav-1 short hairpin RNA significantly reduced S100B-induced inflammatory gene expression in VSMCs. Furthermore, VSMCs derived from insulin-resistant and diabetic db/db mice displayed increased RAGE expression, Src activation, and migration compared with those from control db/؉ mice. The RAGE antibody blocked enhanced migration in db/db cells. These studies demonstrate for the first time that, in VSMCs, Src kinase and Cav-1 play important roles in RAGE-mediated inflammatory gene expression and migration, key events associated with diabetic vascular complications. Vascular smooth muscle cell (VSMC)2 proliferation, migration, and inflammatory gene expression play important roles in the development of atherosclerotic lesions. Diabetic conditions have been shown to enhance these processes, which lead to accelerated atherosclerosis (1-4). Evidence shows that the accumulation of advanced glycation end products (AGEs) and activation of the receptor for AGEs (RAGE) are key factors mediating these events (5-8). RAGE is a member of the immunoglobulin superfamily of cell-surface molecules and is expressed in many cell types, including VSMCs. It can be activated by multiple ligands such as amphoterin, ␤-amyloid peptide, and several short peptides belonging to the S100/calgranulin family, which includes S100B (9, 10). Recent studies using animal models showed that diabetes-induced accelerated atherosclerosis in apoE null mice is associated with enhanced accumulation of RAGE ligands and increased expression of RAGE itself (11, 12). The expression of RAGE as well as its ligands, including S100B, was increased in neointimal and medial cells. Administration of sRAGE could reduce neointimal thickening as well as VSMC proliferation in these animal models. Furthermore, RAGE null mice showed reduced arterial injury responses, whereas transgenic mice expressing DN-RAGE specifically in smooth muscle cells displa...

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Section: Discussionmentioning

confidence: 99%

Key Role of Src Kinase in S100B-induced Activation of the Receptor for Advanced Glycation End Products in Vascular Smooth Muscle Cells

Reddy

Sahar

et al. 2006

Journal of Biological Chemistry

140

121

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“…c-Src is a ubiquitously expressed membrane-associated protein tyrosine kinase that plays important roles in redoxdependent signaling cascades (31,32,104,107,109). As a member of the Src family of nonreceptor protein tyrosine kinases (SFKs), c-Src functions as an important modulator of an array of pathways that transduce signals from the cell surface to the nucleus, including signals promoting cell growth, differentiation, and migration, as well as cellular responses to oxidative stress.…”

Section: Redoxosomal Signaling Via C-src In the Absence Of A Ligand Fmentioning

confidence: 99%

“…In this context, c-Src has been shown to be involved in both ligand-dependent mechanisms of Nox activation (as seen after AngII and aldosterone stimulation) (15,81) and ligand-independent mechanisms of Nox activation (as seen after hypoxia=reoxygenation injury) (69). Furthermore, the redox-activation of Src kinases following hypoxia=reoxygenation injury has been well established (22,31,32,40,105), although the link to Nox activation in this context remains understudied. This section will focus on mechanisms by which c-Src may play a role in the initiation, maintenance, and=or modulation of redoxosome-dependent signaling cascades that utilize NADPH oxidase, with a focus on the mechanisms involved in reoxygenation injury.…”

Section: Redoxosomal Signaling Via C-src In the Absence Of A Ligand Fmentioning

confidence: 99%

“…The proinflammatory (i.e., TNFa and IL-1b) canonical pathway of NFkB activation occurs through IKKdependent phosphorylation of IkBa on Ser 32=36 , which directs IkBa to be degraded by the proteasome. In contrast, NFkB activation following hypoxia=reoxygenation injury is dependent on c-Src-mediated tyrosine phosphorylation of IkBa on Tyr 42 and occurs in a proteasome-independent manner (32,49).…”

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confidence: 96%

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Signaling Components of Redox Active Endosomes: The Redoxosomes

Oakley

Abbott

et al. 2009

Antioxidants & Redox Signaling

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180

160

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Subcellular compartmentalization of reactive oxygen species (ROS) plays a critical role in transmitting cell signals in response to environmental stimuli. In this regard, signals at the plasma membrane have been shown to trigger NADPH oxidase-dependent ROS production within the endosomal compartment and this step can be required for redox-dependent signal transduction. Unique features of redox-active signaling endosomes can include NADPH oxidase complex components (Nox1, Noxo1, Noxa1, Nox2, p47phox, p67phox, and=or Rac1), ROS processing enzymes (SOD1 and=or peroxiredoxins), chloride channels capable of mediating superoxide transport and=or membrane gradients required for Nox activity, and novel redox-dependent sensors that control Nox activity. This review will discuss the cytokine and growth factor receptors that likely mediate signaling through redox-active endosomes, and the common mechanisms whereby they act. Additionally, the review will cover ligand-independent environmental injuries, such as hypoxia=reoxygenation injury, that also appear to facilitate cell signaling through NADPH oxidase at the level of the endosome. We suggest that redox-active endosomes encompass a subset of signaling endosomes that we have termed redoxosomes. Redoxosomes are uniquely equipped with redox-processing proteins capable of transmitting ROS signals from the endosome interior to redox-sensitive effectors on the endosomal surface. In this manner, redoxosomes can control redoxdependent effector functions through the spatial and temporal regulation of ROS as second messengers. Antioxid. Redox Signal. 11, 1313-1333

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“…Unlike the situation in intestinal I/R, where deletion of IKKb in epithelial cells increased the injury (Chen et al, 2003), strong IKK activation is not seen after hepatic I/R (Uchinami et al, 2002). Curiously, NF-kB activation in response to liver I/R is not mediated by the classical IKKb-dependent pathway, and instead depends on tyrosine phosphorylation of IkBa by Src family members (Fan et al, 2004).…”

Section: Introductionmentioning

confidence: 98%