Host cells infected with obligate intracellular bacteria Chlamydia trachomatis are profoundly resistant to diverse apoptotic stimuli. The molecular mechanisms underlying the block in apoptotic signaling of infected cells is not well understood. Here we investigated the molecular mechanism by which apoptosis induced via the tumor necrosis factor (TNF) receptor is prevented in infected epithelial cells. Infection with C. trachomatis leads to the up-regulation of cellular inhibitor of apoptosis (cIAP)-2, and interfering with cIAP-2 up-regulation sensitized infected cells for TNF-induced apoptosis. Interestingly, besides cIAP-2, cIAP-1 and X-linked IAP, although not differentially regulated by infection, are required to maintain apoptosis resistance in infected cells. We detected that IAPs are constitutively organized in heteromeric complexes and small interfering RNA–mediated silencing of one of these IAPs affects the stability of another IAP. In particular, the stability of cIAP-2 is modulated by the presence of X-linked IAP and their interaction is stabilized in infected cells. Our observations suggest that IAPs are functional and stable as heteromers, a thus far undiscovered mechanism of IAP regulation and its role in modulation of apoptosis.
Summary We describe a mechanism by which the anti-apoptotic B-cell lymphoma 2 (Bcl-2) protein is down-regulated to induce apoptosis. ARTS (Sept4_i2) is a tumor suppressor protein that promotes cell death through specifically antagonizing XIAP (X linked Inhibitor of Apoptosis). ARTS and Bcl-2 reside at the outer mitochondrial membrane in living cells. Upon apoptotic induction, ARTS brings XIAP and Bcl-2 into a ternary complex allowing XIAP to promote ubiquitylation and degradation of Bcl-2. ARTS binding to Bcl-2 involves the BH3 domain of Bcl-2. Lysine 17 in Bcl-2 serves as the main acceptor for ubiquitylation and a Bcl-2 K17A mutant has increased stability and is more potent in protection against apoptosis. Bcl-2 ubiquitylation is reduced in both XIAP and Sept4/ARTS deficient MEFs, demonstrating that XIAP serves as an E3-ligase for Bcl-2 and ARTS is essential for this process. Collectively, these results suggest a distinct model for the regulation of Bcl-2 by ARTS-mediated degradation.
It is well accepted that tumor microenvironment is essential for tumor cells survival, cancer progression and metastasis. However, the mechanisms by which tumor cells interact with their surrounding at early stages of cancer development are largely unidentified. The aim of this study was to identify specific molecules involved in stromal-epithelial interactions that might contribute to early stages of prostate tumor formation. Here, we show that conditioned medium (CM) from immortalized non-transformed prostate epithelial cells stimulated immortalized prostate stromal cells to express cancer-related molecules. CM obtained from epithelial cells triggered stromal cells to express and secrete CXCL-1, CXCL-2, CXCL-3 and interleukin (IL)-8 chemokines. This effect was predominantly mediated by the cytokines of the IL-1 family secreted by the epithelial cells. Thus, prostate epithelial cells induced the secretion of proinflammatory and cancer-promoting chemokines by prostate stromal cells. Such interactions might contribute to prostatic inflammation and progression at early stages of prostate cancer formation.
The prostate is composed of a number of different cell populations. The interaction between them is crucial for the development and proper function of the prostate. However, the effect of the molecular cross talk between these cells in the course of carcinogenesis is still unclear. Employing an approach wherein immortalized epithelial cells and immortalized human fibroblasts were cocultured, we show that normal associated fibroblasts
The obligate intracellular human pathogenic bacterium Chlamydia trachomatis has evolved multiple mechanisms to circumvent the host immune system. Infected cells exhibit a profound resistance to the induction of apoptosis and downregulate the expression of major histocompatibility complex class I and class II molecules to evade the cytotoxic effect of effector immune cells. Here we demonstrate the down-regulation of tumor necrosis factor receptor 1 (TNFR1) on the surface of infected cells. Interestingly, other members of the TNFR family such as TNFR2 and CD95 (Fas/Apo-1) were not modulated during infection, suggesting a selective mechanism underlying surface reduction of TNFR1. The observed effect was not due to reduced expression since the overall amount of TNFR1 protein was increased in infected cells. TNFR1 accumulated at the chlamydial inclusion and was shed by the infected cell into the culture supernatant. Receptor shedding depended on the infection-induced activation of the MEK-ERK pathway and the metalloproteinase TACE (TNF␣ converting enzyme). Our results point to a new function of TNFR1 modulation by C. trachomatis in controlling inflammatory signals during infection.Chlamydia trachomatis are obligate intracellular bacteria with a unique biphasic developmental cycle. Infectious elementary bodies enter the cell through endocytosis. Inside the cell elementary bodies mature into non-infectious metabolically active reticulate bodies within a vacuole termed the inclusion. At the end of the cycle, reticulate bodies redevelop into elementary bodies that are released from the cell to start a new infection. C. trachomatis is the most common causative agent of sexually transmitted diseases in the western world. In developing countries it is responsible for trachoma, a form of follicular conjunctivitis passed on by smear infection, which is the leading cause of acquired blindness. Chronic infections with C. trachomatis are associated with inflammatory diseases of the joints including reactive or rheumatoid arthritis (1, 2).The details of how diseases caused by C. trachomatis infection develop are still not fully understood, but immunological responses of the host very likely play a major role (for review, see Ref.3). These involve the secretion of cytokines and chemokines by infiltrating immune cells. One of the best-studied cytokines is interferon ␥ produced by activated T-lymphocytes. It limits chlamydial growth by stimulating the synthesis of indoleamine 2,3-dioxygenase, an enzyme that participates in tryptophan catabolism. Thereby, the availability of tryptophan for the bacteria is limited, resulting in reduced growth (4, 5). Tryptophan limitation induced by interferon ␥ can synergistically be enhanced by tumor necrosis factor ␣ (TNF␣) 2 (6) and reversed by supplying additional tryptophan (7). Chlamydial infection activates macrophages to produce TNF␣ and interferon ␥, which is believed to drive an inflammatory loop especially during a persistent infection (8, 9).However, TNF␣ also blocks chlamydial growth on ...
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