Cyclic AMP and Cyclic GMP suppress TNFα-induced hepatocyte apoptosis by inhibiting FADD up-regulation via a protein kinase A-dependent pathway

Background: iNOS/NO blocks TNF␣-induced apoptosis by cGMP-dependent and cGMP-independent mechanisms in hepatocytes. Result: TLR4-dependent iNOS expression in hepatocytes leads to NO/cGMP/PKG-dependent TACE/ADAM17 and iRhom2 phosphorylation and interaction, TACE/ADAM17 activation/surface translocation, and TNFR1 shedding. Conclusion: iNOS expression leads to rapid TNFR1 shedding through NO/cGMP/PKG-dependent translocation and activation of TACE/ADAM17. Significance: This novel mechanism for iNOS/NO/cGMP-induced TACE activation and translocation may limit TNF␣-mediated signaling.

Section: Discussionmentioning

confidence: 99%

Section: Tumor Necrosis Factor (Tnf)mentioning

confidence: 99%

See 1 more Smart Citation

A Role for cGMP in Inducible Nitric-oxide Synthase (iNOS)-induced Tumor Necrosis Factor (TNF) α-converting Enzyme (TACE/ADAM17) Activation, Translocation, and TNF Receptor 1 (TNFR1) Shedding in Hepatocytes

Chanthaphavong

Loughran

Lee

et al. 2012

“…For example, cAMP analogs promote apoptosis in lymphoid cells (2) but protect certain other cell types from apoptosis; the latter include neurons (1), hepatocytes (33), neutrophils (34), and intestinal epithelial cells (35). In the current study, we used S49 lymphoma cells as a unique model system to investigate how cAMP/PKA induces apoptosis by assessing mechanisms and gene expression patterns that relate to apoptosis in WT S49 cells and in D Ϫ , a mutant S49 cell line that is resistant to apoptosis.…”

Section: Discussionmentioning

confidence: 99%

Gene Expression Signatures of cAMP/Protein Kinase A (PKA)-promoted, Mitochondrial-dependent Apoptosis

Zhang

Zambon

Vranizan

et al. 2008

The ability of the second messenger cAMP to alter the balance between cell growth and apoptosis is cell type-dependent. cAMP stimulates growth and inhibits apoptosis in some cell types, such as neuronal cells (1), but it promotes growth arrest and apoptosis in other types of cells, such as poorly differentiated lymphoid cells (2). In addition, cAMP analogs can enhance the pro-apoptotic effects of glucocorticoids, for example, of glucocorticoid-resistant multiple myeloma and leukemia cells (2-5). However, the mechanisms that mediate cAMP-induced apoptosis are poorly understood.Cyclic AMP-promoted apoptosis of lymphoid, in particular T-cell-derived lymphoma, cells depends on the principal effector of cAMP action, protein kinase A (PKA) 3 (2-4, 6). Although both PKA and the exchange protein directly activated by cyclic AMP (Epac), another mediator of cAMP action, are found in lymphoid cells, Epac does not appear to be involved in cAMPmediated control of the cell cycle (7) or apoptosis in these cells (2,8). Overexpression of certain anti-apoptotic proteins, such as Bcl-2, can protect lymphoma cells from cAMP-mediated apoptosis; such protection appears to be distinct from effects of cAMP on cell cycle arrest (9). Thus, cAMP-promoted growth arrest and apoptosis appear to occur via distinct mechanisms.S49 lymphoma cells are a unique model system to explore cell growth arrest and apoptosis by the cAMP/PKA pathway. S49 cells, which arose in a BALB/c mouse as a T-cell tumor, grow in suspension culture with a doubling time of 14 -16 h and undergo G 1 growth arrest and apoptosis in response to elevation of cAMP (10, 11). S49 clonal variants have been isolated that are resistant to killing by cAMP or agents that increase cAMP levels. One of these cAMP-resistant variants, D Ϫ (cAMP deathless) S49 cells, has normal PKA activity and cAMP-promoted growth arrest in G 1 but lacks cAMP-promoted apoptosis (12). * This work was supported by Grants from the Leukemia and Lymphoma Society, National Institutes of Health (GM61774), and National Institutes of Health sponsored Institutional Research and Academic Career Development Award (IRACDA) fellowship (GM06852). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

“…The second messenger cAMP has cell type-dependent effects on apoptosis (as recently reviewed (1)), being anti-apoptotic in certain cell types (e.g. neutrophils (2), eosinophils (3), hepatocytes (4), gastrointestinal epithelial cells (5), and several others) whereas having proapoptotic actions in other types of cells (e.g. cardiac myocytes (6) and certain lymphoid cells (7), in particular poorly differentiated lymphoblastic cells (8,9)).…”

mentioning

confidence: 99%

Increased Expression of the Pro-apoptotic Protein BIM, a Mechanism for cAMP/Protein Kinase A (PKA)-induced Apoptosis of Immature T Cells

Zambon

Wilderman

et al. 2011

The second messenger cAMP is proapoptotic for numerous cell types, but the mechanism for this proapoptotic action is not defined. Here, we use murine CD4 ؉ /CD8 ؉ S49 lymphoma cells and isolated thymocytes to assess this mechanism. In WT Apoptosis, programmed cell death, contributes to a variety of cellular processes that include embryonic development, tissue homeostasis, and immune responses. Apoptosis can be stimulated by a variety of "death stimuli," including DNA damage, oxidative stress, hormones, cytokines, and drugs and is often targeted in cancer therapy. The second messenger cAMP has cell type-dependent effects on apoptosis (as recently reviewed (1)), being anti-apoptotic in certain cell types (e.g. neutrophils (2), eosinophils (3), hepatocytes (4), gastrointestinal epithelial cells (5), and several others) whereas having proapoptotic actions in other types of cells (e.g. cardiac myocytes (6) and certain lymphoid cells (7), in particular poorly differentiated lymphoblastic cells (8, 9)). Hematological malignancies, including large B cell lymphoma and chronic lymphocytic leukemia, are associated with a deficiency in apoptosis (10, 11). We and others have implicated the cAMP/PKA pathway as a promising one to enhance killing of lymphoma and leukemia cells (7,8,(12)(13)(14). Despite the proapoptotic ability of cAMP/PKA, the mechanisms for this action are poorly defined.Using murine S49 lymphoma cells, CD4 ϩ /CD8 ϩ T cells that undergo growth arrest in the G 1 phase of the cell cycle and apoptosis in response to cAMP-promoted activation of PKA 2 (15), we identified mRNAs that differ between WT and kin-S49 cells, which lack PKA (16). In other studies, we showed that expression of certain apoptotic pathway members are differentially regulated in WT and cAMP-deathless (D-) S49 cells (7, 12), a clonal isolate that undergoes G 1 arrest but is resistant to cAMP/PKA-promoted apoptosis (17).The proapoptotic protein Bim, a BH3-only Bcl family member protein, shows a pronounced difference in expression between 12), with Bim expression being higher and longer in the WT cells treated with a cAMP analog or with a ␤-adrenergic agonist; moreover, increase in cAMP does not increase Bim expression in kin-cells (7,12). Bim triggers apoptosis by promoting the release of cytochrome C from mitochondria. However, Bim may not be sufficient for inducing apoptosis, which can involve other BH3-only proteins (18). Multiple Bim isoforms exist (19), certain of which have been implicated in promoting T cell and B cell apoptosis (20). In this study, we used S49 cells (WT, D-, and kin-mutants) and CD4 ϩ / CD8 ϩ thymocytes isolated from WT and Bim Ϫ/Ϫ mice to test whether Bim mediates cAMP/PKA-promoted apoptotic cell death in CD4 ϩ /CD8 ϩ cells. EXPERIMENTAL PROCEDURESMaterials-WT, kin-, and D-S49 cells were obtained from the University of San Francisco cell culture facility. 8-(4-chlorophenylthio)-adenosine-3Ј,5Ј-cyclic monophosphate (CPTcAMP) was obtained from Sigma-Aldrich. BimL cDNA was purchased from Addgene (21). Protease inhibitor m...