High density lipoprotein (HDL) is the major atheroprotective particle in plasma. Recent studies demonstrate that myeloperoxidase (MPO) binds to HDL in vivo, selectively targeting apolipoprotein A1 (apoA1) of HDL for oxidative modification and concurrent loss in cholesterol efflux and lecithin cholesterol acyl transferase activating activities, generating a "dysfunctional HDL" particle. We now show that (patho)physiologically relevant levels of MPO-catalyzed oxidation result in loss of noncholesterol efflux activities of HDL including anti-apoptotic and anti-inflammatory functions. One mechanism responsible is shown to involve the loss of modified HDL binding to the HDL receptor, scavenger receptor B1, and concurrent acquisition of saturable and specific binding to a novel unknown receptor independent of scavenger receptors CD36 and SR-A1. HDL modification by MPO is further shown to confer pro-inflammatory gain of function activities as monitored by NF-B activation and surface vascular cell adhesion molecule levels on aortic endothelial cells exposed to MPO-oxidized HDL. The loss of non-cholesterol efflux activities and the gain of pro-inflammatory functions requires modification of the entire particle and can be recapitulated by oxidation of reconstituted HDL particles comprised of apoA1 and nonoxidizable phosphatidylcholine species. Multiple site-directed mutagenesis studies of apoA1 suggest that the pro-inflammatory activity of MPO-modified HDL does not involve methionine, tyrosine, or tryptophan, oxidant-sensitive residues previously mapped as sites of apoA1 oxidation within human atheroma. Thus, MPO-catalyzed oxidation of HDL results not only in the loss of classic atheroprotective reverse cholesterol transport activities of the lipoprotein but also both the loss of non-cholesterol efflux related activities and the gain of pro-inflammatory functions. High density lipoprotein (HDL)3 is a complex mixture of cholesterol carrying lipoprotein particles built upon a predominantly apolipoprotein A1 (apoA1) backbone. HDL is currently thought to function primarily in mediating reverse cholesterol transport (RCT), the net transport of cholesterol from peripheral tissues to the liver for ultimate elimination into the intestinal lumen as biliary cholesterol for excretion in feces (1). RCT involves multiple biochemical processes, including both lipid poor apoA1 and HDL serving as acceptors of cholesterol efflux from peripheral cholesterol loaded cells, maturation of HDL from a nascent relatively cholesterol poor particle into a cholesterol-laden spherical form through interaction with lecithin cholesterol acyl transferase (LCAT), and delivery of cholesterol to liver and steroidogenic tissues through the HDL receptor, scavenger receptor B1 (SR-B1) (2).Although the RCT related functions of apoA1 and HDL are thought to primarily account for both the atheroprotective activity and the strong inverse association of HDL cholesterol and apoA1 levels and cardiovascular risks, other non-cholesterol efflux-related activities have a...
Background: Infection of intestinal epithelial cells by pathogenic Salmonella leads to activation of signaling cascades that ultimately initiate the proinflammatory gene program. The transcription factor NF-κB is a key regulator/activator of this gene program and is potently activated. We explored the mechanism by which Salmonella activates NF-κB during infection of cultured intestinal epithelial cells and found that flagellin produced by the bacteria and contained on them leads to NF-κB activation in all the cells; invasion of cells by the bacteria is not required to activate NF-κB.
We have previously demonstrated the anti-tumor activity of nitrosylcobalamin (NO-Cbl), an analog of vitamin B12 that delivers nitric oxide (NO) and increases the expression of tumor necrosis factor-related apoptosis-inducing ligand (Apo2L/TRAIL) and its receptors in human tumors. The specific aim of this study was to examine whether NO-Cbl could sensitize drug-resistant melanomas to Apo2L/TRAIL. Antiproliferative effects of NO-Cbl and Apo2L/TRAIL were assessed in malignant melanomas and non-tumorigenic melanocyte and fibroblast cell lines. Athymic nude mice bearing human melanoma A375 xenografts were treated with NO-Cbl and Apo2L/TRAIL. Apoptosis was measured by TUNEL and confirmed by examining levels and activity of key mediators of apoptosis.
We previously showed that inositol hexakisphosphate kinase 2 (IHPK2) functions as a growth-suppressive and apoptosis-enhancing kinase during cell stress. Overexpression of IHPK2 sensitized ovarian carcinoma cell lines to the growth-suppressive and apoptotic effects of interferon  (IFN-), IFN-␣2, and ␥-irradiation. Expression of a kinase-dead mutant abrogated 50% of the apoptosis induced by IFN-. Because the kinase-dead mutant retained significant response to cell stressors, we hypothesized that a portion of the death-promoting function of IHPK2 was independent of its kinase activity. We now demonstrate that IHPK2 binds to tumor necrosis factor (TNF) receptor-associated factor (TRAF) 2 and interferes with phosphorylation of transforming growth factor -activated kinase 1 (TAK1), thereby inhibiting NF-B signaling. Inositol polyphosphates play diverse biologic roles, including regulation of endocytic trafficking (1), protein phosphorylation (2), chemotaxis (3), regulation of non-homologous end joining (4 -6), and apoptosis (7,8). Inositol hexakisphosphate kinase 2 (IHPK2) 2 is a kinase that catalyzes the synthesis of diphosphoinositol pentakisphosphate and bis-diphosphoinositol tetrakisphosphate. Overexpression of IHPK2 sensitizes ovarian carcinoma cell lines to the growth-suppressive and apoptotic effects of IFN-, IFN-␣2 treatment, and ionizing radiation (9). Snyder and co-workers (8) recently demonstrated that IHPK2 enhanced the cytotoxic actions of several different cell stressors.By co-immunoprecipitation, we found that IHPK2 associated with TRAF2. The tumor necrosis factor (TNF) receptorassociated factor (TRAF) family of proteins serve as adapter proteins for the TNF-R and interleukin-1 receptor superfamilies (10, 11). The role of TRAF2 in mediating the TNF-␣ response is controversial. Early studies with TRAF2 and TRAF5 knock-out mice or dominant negative (DN) TRAF2 mice suggested that these proteins were not essential or played redundant roles in TNF-induced . TRAF2 Ϫ/Ϫ fibroblasts are severely impaired in their ability to activate c-Jun N-terminal kinase in response to TNF-␣ (12). Subsequent studies suggested that TRAF2 Ϫ/Ϫ fibroblasts (15) or TRAF2/TRAF5 double knock-out murine fibroblasts (16) were impaired in their ability to activate NF-B in response to TNF-␣. Most recently, Aggarwal and co-workers (17) have shown that NF-B activation in carcinomas could be disrupted by expression of DN-TRAF2 but not by DN-TRAF5, suggesting that TRAF2 plays a critical role in TNF-␣-induced NF-B activation.Within the trimeric signaling complex TRAF2 serves to recruit IB kinase (IKK) and RIP1 to the TNF-R1 (18,19). Transforming growth factor -activated kinase (TAK1) is a critical component of this cascade, functioning downstream of RIP1 and TRAF2 to activate IKK (20). We hypothesized that the binding of IHPK2 to TRAF2 might disrupt TNF-␣ signaling. The aims of this study were to identify motifs in IHPK2 required for TRAF2 binding and to determine whether disruption of IHPK2-TRAF2 binding would affect TNF-␣ signaling.
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