Celia A Sigua

University of South Florida, Tampa, FL, United States

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Publications (4)11.47 Total impact

  • Yanhua Peng, Celia A Sigua, Michel M Murr
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    ABSTRACT: We have demonstrated that activated Kupffer cells undergo accelerated apoptosis via Toll-like receptor (TLR)-4 and protein kinase C (PKC)-ζ-dependent nuclear factor (NF)-κB activation. Because PKC-ζ plays a pivotal role in cell signaling, we sought to determine the signaling pathway of PKC-ζ in Kupffer cell apoptosis. Mouse Kupffer cell line (MKCL3-2) were transfected with PKC-ζ small interfering RNA (siRNA) and then treated with elastase alone or elastase along with the extracellular signal-regulated kinase (ERK) inhibitor U0126. Cell extracts were assayed for PKC-ζ (protein and activity), TLR-4, NF-κB nuclear translocation, phosphorylated ERK-1/2, activated caspase-3, and DNA fragmentation. All n ≥3; data are expressed as mean values ± standard deviations; means were compared using the t test; P < .05 was considered significant. Elastase upregulated TLR-4, PKC-ζ, NF-κB, ERK-1/2, caspase-3, and DNA fragmentation (all P < .01 versus control). Transfection with PKC-ζ siRNA attenuated the elastase-induced upregulation of PKC-ζ activity, NF-κB, ERK-1/2, caspase-3, and DNA fragmentation (all P < .01 versus control). The interaction of PKC-ζ with ERK-1/2 was increased by elastase and was attenuated by PKC-ζ siRNA as confirmed by co-immunoprecipitation and immunofluorescent staining. Activation of Kupffer cells upregulates PKC-ζ activity, increases apoptosis, and induces nuclear translocation of NF-κB via ERK-1/2-dependent pathways. Inhibiting the activity of PKC-ζ significantly attenuates Kupffer cell apoptosis, NF-κB, and ERK-1/2 activation. The interaction of PKC-ζ and ERK-1/2 warrants further investigation.
    Surgery 01/2011; 149(1):135-42. · 3.37 Impact Factor
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    ABSTRACT: Toll-like receptor-4 (TLR4) and protein kinase C-zeta (PKC-zeta) play a role in macrophage activation. We hypothesized that deletion of TLR4 downregulates PKC-zeta and attenuates liver cell apoptosis in experimental pancreatitis. Acute pancreatitis was induced by choline-deficient ethionine diet in C57/BL6 (TLR4+/+ and TLR4-/-) mice. During pancreatitis, staining for TLR4 and PKC-zeta, which colocalized in Kupffer cells but not in hepatocytes, increased in TLR4+/+ mice and decreased in TLR4-/- mice. In TLR4+/+ mice, pancreatitis increased TLR4 protein and mRNA and PKC-zeta protein and activity, nuclear factor (NF)-kappaB, ERK1/2, caspase-3 cleavage, and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) staining; all P < .01 versus controls. In TLR4-/- mice with pancreatitis, PKC-zeta mRNA and activity were reduced, ERK1/2 and caspase-3 did not increase, and NF-kappaB and TUNEL (mostly in hepatocytes) increased mildly (all P < .01 vs control). PKC-zeta did not interact directly with NF-kappaB; however, during pancreatitis, coimmunoprecipitation of PKC-zeta with ERK1/2 was increased in TLR4+/+ mice and was attenuated in TLR4-/- mice (all P < .01 vs control), indicating that PKC-zeta interacts with ERK1/2. Acute pancreatitis upregulates TLR4, PKC-zeta, NF-kappaB, and ERK1/2, and increases apoptosis in mice livers. PKC-zeta induces nuclear translocation of NF-kappaB via ERK1/2-dependent mechanisms. Deletion of TLR4 downregulates PKC-zeta, NF-kappaB, and ERK1/2, and attenuates pancreatitis-induced liver cell apoptosis.
    Surgery 05/2008; 143(5):679-85. · 3.37 Impact Factor
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    ABSTRACT: Kupffer cells play an important role in sepsis-mediated liver injury. We tested the hypothesis that PKC-zeta plays a critical role in Kupffer cell apoptosis during sepsis. Sepsis was induced in rats by cecal ligation and puncture (CLP); 12 h later, livers were assayed for PKC-zeta, IKKalpha, IKKbeta, IKKgamma, NF-kappaB, Fas/FasL, Caspase-3, and DNA fragmentation. Kupffer cells from control rats were infected with AdPKC-zeta DN to inhibit PKC-zeta, or transfected with pCMVPKC-zeta to overexpress PKC-zeta, and then treated with lipopolysaccharide (LPS). Cellular extracts were assayed for PKC-zeta, IKKalpha, IKKbeta, IKKgamma, NF-kappaB, Fas/FasL, Caspase-3, and DNA fragmentation. During sepsis, PKC-zeta localized in cells positive for the macrophage marker (F4/80). CLP upregulated PKC-zeta protein and activity, IKKbeta, IKKgamma, NF-kappaB, Fas/FasL, Caspase-3, and increased DNA fragmentation in rat livers (all p<0.001). AdPKC-zeta DN attenuated the LPS-induced upregulation of PKC-zeta activity, IKKbeta, IKKgamma, NF-kappaB, Fas/FasL, Caspase-3, and DNA fragmentation in Kupffer cells (all p<0.001), whereas overexpression of PKC-zeta augmented LPS-induced upregulation of IKKbeta, IKKgamma, NF-kappaB, Caspase-3, and DNA fragmentation (p<0.001). PKC-zeta plays an important role in sepsis-induced apoptosis of Kupffer cells via activation of NF-kappaB and Fas/FasL. Manipulating the response of Kupffer cells to cellular stress may have important therapeutic implications.
    Journal of Gastrointestinal Surgery 01/2008; 11(12):1712-21. · 2.36 Impact Factor
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    ABSTRACT: Protein kinase C-zeta (PKC-zeta) regulates cell death via NF-kappaB; therefore, we tested the hypothesis that PKC-zeta plays a critical role in pancreatitis-induced Kupffer cell apoptosis. Acute pancreatitis was induced in rats by cerulein injection 24 h later, livers were assayed for PKC-zeta, IKKalpha, IKKbeta, IKKgamma, NF-kappaB, Fas/FasL, and apoptosis was assessed with Caspase-3 and DNA fragmentation. Kupffer cells from unoperated rats were infected with a PKC-zeta domain-negative adenovirus (AdPKCzeta-DN) to inhibit PKC-zeta, or transfected with pCMVPKC-zeta to overexpress PKC-zeta, and then stimulated with pancreatic elastase; cellular extracts were assayed for PKC-zeta, IKKalpha, IKKbeta, IKKgamma, NF-kappaB, Fas/FasL, Caspase-3, and DNA fragmentation. Cerulein-induced pancreatitis upregulated PKC-zeta protein and activity, IKKbeta, IKKgamma, NF-kappaB, Fas/FasL, Caspase-3 and increased DNA fragmentation in rat livers (all p < 0.001 vs control). AdPKCzeta-DN abolished elastase-induced upregulation of PKC-zeta activity, IKKbeta, IKKgamma, NF-kappaB, Fas/FasL, Caspase-3 and DNA fragmentation (all p < 0.001 vs infection control), whereas overexpression of PKC-zeta augmented elastase-induced upregulation of IKKbeta, IKKgamma, Fas/FasL, Caspase-3 and DNA fragmentation (p < 0.001 vs control). PKC-zeta plays a critical role in pancreatitis-induced Kupffer cell apoptosis via NF-kappaB and Fas/FasL. The ability of Kupffer cells to autoregulate their stress response by upregulating their death receptor/ligand and key proapoptotic cell signaling systems warrants further investigation.
    Journal of Gastrointestinal Surgery 10/2007; 11(10):1253-61. · 2.36 Impact Factor

Publication Stats

30 Citations
11.47 Total Impact Points

Institutions

  • 2007–2011
    • University of South Florida
      • Department of Surgery
      Tampa, FL, United States
  • 2008
    • James A. Haley Veterans Hospital
      Tampa, Florida, United States
    • Tampa General Hospital
      Tampa, Florida, United States