Chlamydia pneumoniae activates IKK/I kappa B-mediated signaling, which is inhibited by 4-HNE and following primary exposure.
Institute of Clinical Chemistry and Pathobiochemistry, Technische Universität München, Klinikum rechts der Isar, Ismaninger Strasse 22, 81675 München, Germany. Atherosclerosis
(Impact Factor: 3.99).
Chlamydia pneumoniae may be involved in atherosclerosis by inducing inflammation as well as LDL oxidation. The transcription factor NF-kappa B is found in an active state in atherosclerotic lesions. This study examined the effect of C. pneumoniae exposure on the NF-kappa B system in human monocytic lineage cells. Short exposure to C. pneumoniae as well as chlamydial heat shock protein 60 activated NF-kappa B, accompanied by increased cytokine production. Incubation with C. pneumoniae-induced depletion of I kappa B-alpha and later I kappa B-epsilon which was preceded by I kappa B kinase complex activation. 4-Hydroxynonenal, an aldehyde LDL oxidation product, was shown to inhibit C. pneumoniae induced NF-kappa B activation by preventing I kappa B phosphorylation/proteolysis. During long-term incubation with C. pneumoniae I kappa B-alpha returned to baseline, whereas the levels of I kappa B-epsilon and p65 were upregulated. Interestingly, long-term preincubation with C. pneumoniae selectively prevented restimulation by this microorganism, which appears to be at least partly facilitated by inhibition of I kappa B proteolysis. C. pneumoniae-induced NF-kappa B activation as well as the inhibition of that effect under certain conditions may contribute to chronic inflammation with potential relevance to vascular disease.
Available from: Tugsan Tezil
- "While IKKb was shown to mediate Bcl-x L downregulation and subsequent caspase activation via directly phosphorylating Bcl-x L in neurons; IKKa, which has a nuclear localization sequence that IKKb lacks, was demonstrated to regulate neural inflammation transcriptionally in a subset of T-cells (Khoshnan et al., 2009; Li et al., 2011). Of note, HNE was previously reported to decrease IkBa phosphorylation ability of IKK complexes immunoprecipitated from cell extracts (Ji et al., 2001; Donath et al., 2002). In this light, which is in concert with our finding that cellular P-IkBa levels slightly decrease upon HNE induction, attenuation of pro-survival transcriptional activity of NF-kB may also contribute to cell death in U937 cells. "
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ABSTRACT: Apoptosis of macrophage foam cells loaded with modified/oxidized lipids is implicated in destabilization of advanced atherosclerotic plaques in humans. Concentration of HNE, main aldehydic product of plasma LDL peroxidation, elevates in atherosclerotic lesions as well as in cultured cells under oxidative stress. Although this reactive aldehyde has been shown to promote apoptosis with the involvement of p38 MAPK and JNK in various mammalian cell lines, roles of B-cell lymphoma 2 (Bcl-2) family proteins remain to be deciphered. We demonstrated that HNE-induced apoptosis was accompanied by concurrent downregulations of antiapoptotic Bcl-x(L) and Mcl-1 as well as upregulation of proapoptotic Bak. Furthermore, phoshorylation of Bcl-2 at Thr56, Ser70, and probably more phosphorylation sites located on N-terminal loop domain associated with HNE-induced apoptosis in both U937 and HeLa cells while ectopic expression of a phospho-defective Bcl-2 mutant significantly attenuated apoptosis. In parallel to this, HNE treatment caused release of proapoptotic Bax from Bcl-2. Pharmacological inhbition of IKK inhibited HNE-induced Bcl-2 phosphorylation. Similarly, silencing IKKα and -β both ended up with abrogation of Bcl-2 phosphorylation along with attenuation of apoptosis. Moreover, both IKKα and -β coimmunoprecipitated with Bcl-2 and in vitro kinase assay proved the ability of IKK to phosphorylate Bcl-2. In view of these findings and considering HNE inhibits DNA-binding activity of nuclear factor-κB (NF-κB) through prevention of IκB phosphorylation/ubiquitination/proteolysis, IKK appears to directly interfere with Bcl-2 activity through phosphorylation in HNE-mediated apoptosis independent of NF-κB signaling.
Journal of Cellular Physiology 11/2012; 227(11):3556-65. DOI:10.1002/jcp.24057 · 3.84 Impact Factor
Available from: uic.edu
- "Hydroxyalkenals affect NF-kB signal transduction, a major signaling pathway linked to oxidative stress and inflammation in mammalian cells. Chlamydia pneumonia or LPSactivated IKK/I kappa B-mediated signaling was inhibited by primary exposure to 4-HNE (Donath et al., 2002; Page et al., 1999). This inhibitory effect of 4-HNE seems to involve direct interaction and covalent adduct formation between 4-HNE and IkB proteins with subsequent blockage of phosphorylation and degradation of IkB proteins (Ji et al., 2001). "
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ABSTRACT: Lipid peroxidation of polyunsaturated fatty acids generates bioactive aldehydes, which exhibit pro- and anti-inflammatory effects in cells and tissues. Accumulating evidence indicates that 4-hydroxynonenal (4-HNE), a major aldehyde derived from lipid peroxidation of n-6 polyunsaturated fatty acids trigger signals that modulates focal adhesion and adherens junction proteins thereby inducing endothelial barrier dysfunction. Similarly, oxidized phospholipids (Ox-PLs) generated by lipid peroxidation of phospholipids with polyunsaturated fatty acids have been implicated in atherogenesis, inflammation and gene expression. Interestingly, physiological concentration of Ox-PLs is anti-inflammatory and protect against endotoxin- and ventilator-associated acute lung injury. Thus, excess generation of bioactive hydroxyalkenals and Ox-PLs during oxidative stress contributes to pathophysiology of various diseases by modulating signaling pathways that regulate pro- and anti-inflammatory responses and barrier regulation. This review summarizes the role of 4-HNE and Ox-PLs affecting cell signaling pathways and endothelial barrier dysfunction through modulation of the activities of proteins/enzymes by Michael adducts formation, enhancing the level of protein tyrosine phosphorylation of the target proteins, and by reorganization of cytoskeletal, focal adhesion, and adherens junction proteins. A better understanding of molecular mechanisms of hydroxyalkenals- and Ox-PLs-mediated pro-and anti-inflammatory responses and barrier function may lead to development of novel therapies to ameliorate oxidative stress related cardio-pulmonary disorders.
Microvascular Research 05/2011; 83(1):45-55. DOI:10.1016/j.mvr.2011.04.012 · 2.13 Impact Factor
Available from: Nicole Paland
- "Our data on the NF-κB-induced upregulation of cIAP-2 protein and the requirement of cIAP-1 and cIAP-2 for maintaining the apoptosis resistance, however, suggest an additional level of regulation. The finding that NF-κB is required for apoptosis resistance is particularly interesting because acute C. pneumoniae has been shown to induce the translocation of NF-κB in a variety of cell lines, for example, in monocytes (Wahl et al., 2001; 2003; Donath et al., 2002), in epithelial cell lines HL and Calu3 (Gencay et al., 2003), in human smooth muscle cells (Dechend et al., 1999; Miller et al., 2000) and in endothelial cells (Dechend et al., 1999; Krull et al., 1999; Molestina et al., 2000; Baer et al., 2003). Thus, an involvement of NF-κB in Cpn infection-induced apoptosis resistance of other cell types is very likely. "
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ABSTRACT: Infection with Chlamydophila pneumoniae (Cpn) renders host cells resistant to apoptosis induced by a variety of stimuli. While modulation of apoptosis has been extensively studied in cells acutely infected with Cpn, very little is known on how persistent chlamydial infection influences host cell survival. Here we show that epithelial cells persistently infected with Cpn resist apoptosis induced with TNFalpha or staurosporine. Cpn induced the activation of nuclear factor kappa B (NF-kappaB) and inhibition of NF-kappaB with a chemical inhibitor or by silencing expression of the p65 subunit sensitized infected cells for apoptosis induction by staurosporine or TNFalpha. Persistent infection resulted in the upregulation of the NF-kappaB regulated inhibitor of apoptosis protein 2 (cIAP-2) but not inhibitor of apoptosis protein 1 (cIAP-1). Interestingly, silencing of either cIAP-1 or cIAP-2 sensitized infected cells, suggesting that IAPs play an important role in the apoptosis resistance of persistently infected cells.
Cellular Microbiology 11/2006; 8(10):1643-55. DOI:10.1111/j.1462-5822.2006.00739.x · 4.92 Impact Factor
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