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Deadly liaisons: fatal attraction between CCN matricellular proteins and the tumor necrosis factor family of cytokines.

Chen CC, Lau LF - J Cell Commun Signal (2009)

Bottom Line: Mechanistically, CCNs function through integrin alpha(6)beta(1) and the heparan sulfate proteoglycan (HSPG) syndecan-4 to induce reactive oxygen species (ROS) accumulation, which is essential for apoptotic synergism.Mutant CCN1 proteins defective for binding alpha(6)beta(1)-HSPGs are unable to induce ROS or apoptotic synergism with TNF cytokines.Further, knockin mice that express an alpha(6)beta(1)-HSPG-binding defective CCN1 are blunted in TNFalpha- and Fas-mediated apoptosis, indicating that CCN1 is a physiologic regulator of these processes.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry and Molecular Genetics, College of Medicine, University of Illinois at Chicago, Chicago, IL 60607 USA.

ABSTRACT
Recent studies have revealed an unexpected synergism between two seemingly unrelated protein families: CCN matricellular proteins and the tumor necrosis factor (TNF) family of cytokines. CCN proteins are dynamically expressed at sites of injury repair and inflammation, where TNF cytokines are also expressed. Although TNFalpha is an apoptotic inducer in some cancer cells, it activates NFkappaB to promote survival and proliferation in normal cells, and its cytotoxicity requires inhibition of de novo protein synthesis or NFkappaB signaling. The presence of CCN1, CCN2, or CCN3 overrides this requirement and unmasks the apoptotic potential of TNFalpha, thus converting TNFalpha from a proliferation-promoting protein into an apoptotic inducer. These CCN proteins also enhance the cytotoxicity of other TNF cytokines, including LTalpha, FasL, and TRAIL. Mechanistically, CCNs function through integrin alpha(6)beta(1) and the heparan sulfate proteoglycan (HSPG) syndecan-4 to induce reactive oxygen species (ROS) accumulation, which is essential for apoptotic synergism. Mutant CCN1 proteins defective for binding alpha(6)beta(1)-HSPGs are unable to induce ROS or apoptotic synergism with TNF cytokines. Further, knockin mice that express an alpha(6)beta(1)-HSPG-binding defective CCN1 are blunted in TNFalpha- and Fas-mediated apoptosis, indicating that CCN1 is a physiologic regulator of these processes. These findings implicate CCN proteins as contextual regulators of the inflammatory response by dictating or enhancing the cytotoxicity of TNFalpha and related cytokines.

No MeSH data available.


Related in: MedlinePlus

CCN1 is critical for TNFα and Fas-mediated apoptosis in vivo. Ccn1dm/dm knockin mice express the CCN1 mutant DM, which is disrupted in the binding sites for α6β1 and HSPGs and is therefore unable to induce ROS or apoptosis. TNFα-induced apoptosis was tested by either direct subcutaneous injection of TNFα, or by treatment with ConA, which induces TNFα production from macrophages (Chen et al. 2007). Fas-mediated apoptosis was tested by tail-vein injection of the agonistic mAb, Jo2, or by a gavage of ethanol. In each scenario, apoptosis is reduced by 60–70% in Ccn1dm/dm mice compared to wild type mice, indicating that CCN1 is critical for optimal TNFα and Fas-mediated apoptosis in vivo
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Fig5: CCN1 is critical for TNFα and Fas-mediated apoptosis in vivo. Ccn1dm/dm knockin mice express the CCN1 mutant DM, which is disrupted in the binding sites for α6β1 and HSPGs and is therefore unable to induce ROS or apoptosis. TNFα-induced apoptosis was tested by either direct subcutaneous injection of TNFα, or by treatment with ConA, which induces TNFα production from macrophages (Chen et al. 2007). Fas-mediated apoptosis was tested by tail-vein injection of the agonistic mAb, Jo2, or by a gavage of ethanol. In each scenario, apoptosis is reduced by 60–70% in Ccn1dm/dm mice compared to wild type mice, indicating that CCN1 is critical for optimal TNFα and Fas-mediated apoptosis in vivo

Mentions: To study TNF cytokine-mediated cytotoxicity in vivo, Ccn1dm/dm mice were tested in three different models of hepatotoxin-induced apoptosis: intravenous delivery of concanavalin A (ConA), intravenous injection of an agontistic monoclonal antibody that activates Fas (clone Jo2), and intragastric administration of alcohol. ConA induces robust TNFα synthesis in macrophages and T cells and leads to massive TNFα-dependent hepatocyte apoptosis, which is completely abrogated by neutralizing antibodies against TNFα or by genetic ablation of TNFR1 and TNFR2 (Trautwein et al. 1998; Wolf et al. 2001). To examine Fas-mediated apoptosis, the monoclonal antibody Jo2 recognizes and activates the Fas receptor to induce Fas-mediated apoptosis, a process that is annihilated by genetic disruption of Fas, demonstrating the specificity for Fas (Ogasawara et al. 1993). In addition, ethanol gavage in mice mimics binge drinking and results in FasL-induced hepatocyte apoptosis that is ablated by neutralizing antibodies against FasL (Zhou et al. 2001). In all three experimental models, Ccn1dm/dm mice consistently show >60% reduction in hepatocyte apoptosis compared to wild-type mice (Fig. 5) (Juric et al. 2009; Chen et al. 2007). These results show that CCN1 is a physiological regulator of TNFα and Fas-mediated apoptosis in vivo, and suggest an important role for CCN1 in the pathogenesis of toxin-induced hepatitis. However, these findings do not exclude the participation of other factors such as IFNγ, which may regulate TNF cytokine cytotoxicity in certain contexts.Fig. 5


Deadly liaisons: fatal attraction between CCN matricellular proteins and the tumor necrosis factor family of cytokines.

Chen CC, Lau LF - J Cell Commun Signal (2009)

CCN1 is critical for TNFα and Fas-mediated apoptosis in vivo. Ccn1dm/dm knockin mice express the CCN1 mutant DM, which is disrupted in the binding sites for α6β1 and HSPGs and is therefore unable to induce ROS or apoptosis. TNFα-induced apoptosis was tested by either direct subcutaneous injection of TNFα, or by treatment with ConA, which induces TNFα production from macrophages (Chen et al. 2007). Fas-mediated apoptosis was tested by tail-vein injection of the agonistic mAb, Jo2, or by a gavage of ethanol. In each scenario, apoptosis is reduced by 60–70% in Ccn1dm/dm mice compared to wild type mice, indicating that CCN1 is critical for optimal TNFα and Fas-mediated apoptosis in vivo
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2821476&req=5

Fig5: CCN1 is critical for TNFα and Fas-mediated apoptosis in vivo. Ccn1dm/dm knockin mice express the CCN1 mutant DM, which is disrupted in the binding sites for α6β1 and HSPGs and is therefore unable to induce ROS or apoptosis. TNFα-induced apoptosis was tested by either direct subcutaneous injection of TNFα, or by treatment with ConA, which induces TNFα production from macrophages (Chen et al. 2007). Fas-mediated apoptosis was tested by tail-vein injection of the agonistic mAb, Jo2, or by a gavage of ethanol. In each scenario, apoptosis is reduced by 60–70% in Ccn1dm/dm mice compared to wild type mice, indicating that CCN1 is critical for optimal TNFα and Fas-mediated apoptosis in vivo
Mentions: To study TNF cytokine-mediated cytotoxicity in vivo, Ccn1dm/dm mice were tested in three different models of hepatotoxin-induced apoptosis: intravenous delivery of concanavalin A (ConA), intravenous injection of an agontistic monoclonal antibody that activates Fas (clone Jo2), and intragastric administration of alcohol. ConA induces robust TNFα synthesis in macrophages and T cells and leads to massive TNFα-dependent hepatocyte apoptosis, which is completely abrogated by neutralizing antibodies against TNFα or by genetic ablation of TNFR1 and TNFR2 (Trautwein et al. 1998; Wolf et al. 2001). To examine Fas-mediated apoptosis, the monoclonal antibody Jo2 recognizes and activates the Fas receptor to induce Fas-mediated apoptosis, a process that is annihilated by genetic disruption of Fas, demonstrating the specificity for Fas (Ogasawara et al. 1993). In addition, ethanol gavage in mice mimics binge drinking and results in FasL-induced hepatocyte apoptosis that is ablated by neutralizing antibodies against FasL (Zhou et al. 2001). In all three experimental models, Ccn1dm/dm mice consistently show >60% reduction in hepatocyte apoptosis compared to wild-type mice (Fig. 5) (Juric et al. 2009; Chen et al. 2007). These results show that CCN1 is a physiological regulator of TNFα and Fas-mediated apoptosis in vivo, and suggest an important role for CCN1 in the pathogenesis of toxin-induced hepatitis. However, these findings do not exclude the participation of other factors such as IFNγ, which may regulate TNF cytokine cytotoxicity in certain contexts.Fig. 5

Bottom Line: Mechanistically, CCNs function through integrin alpha(6)beta(1) and the heparan sulfate proteoglycan (HSPG) syndecan-4 to induce reactive oxygen species (ROS) accumulation, which is essential for apoptotic synergism.Mutant CCN1 proteins defective for binding alpha(6)beta(1)-HSPGs are unable to induce ROS or apoptotic synergism with TNF cytokines.Further, knockin mice that express an alpha(6)beta(1)-HSPG-binding defective CCN1 are blunted in TNFalpha- and Fas-mediated apoptosis, indicating that CCN1 is a physiologic regulator of these processes.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry and Molecular Genetics, College of Medicine, University of Illinois at Chicago, Chicago, IL 60607 USA.

ABSTRACT
Recent studies have revealed an unexpected synergism between two seemingly unrelated protein families: CCN matricellular proteins and the tumor necrosis factor (TNF) family of cytokines. CCN proteins are dynamically expressed at sites of injury repair and inflammation, where TNF cytokines are also expressed. Although TNFalpha is an apoptotic inducer in some cancer cells, it activates NFkappaB to promote survival and proliferation in normal cells, and its cytotoxicity requires inhibition of de novo protein synthesis or NFkappaB signaling. The presence of CCN1, CCN2, or CCN3 overrides this requirement and unmasks the apoptotic potential of TNFalpha, thus converting TNFalpha from a proliferation-promoting protein into an apoptotic inducer. These CCN proteins also enhance the cytotoxicity of other TNF cytokines, including LTalpha, FasL, and TRAIL. Mechanistically, CCNs function through integrin alpha(6)beta(1) and the heparan sulfate proteoglycan (HSPG) syndecan-4 to induce reactive oxygen species (ROS) accumulation, which is essential for apoptotic synergism. Mutant CCN1 proteins defective for binding alpha(6)beta(1)-HSPGs are unable to induce ROS or apoptotic synergism with TNF cytokines. Further, knockin mice that express an alpha(6)beta(1)-HSPG-binding defective CCN1 are blunted in TNFalpha- and Fas-mediated apoptosis, indicating that CCN1 is a physiologic regulator of these processes. These findings implicate CCN proteins as contextual regulators of the inflammatory response by dictating or enhancing the cytotoxicity of TNFalpha and related cytokines.

No MeSH data available.


Related in: MedlinePlus