Browsing by Subject "Disease Models, Animal"

Filter results by typing the first few letters
Now showing 1 - 2 of 2
  • Thumbnail Image
    ItemOpen Access
    Jnk1 deficiency in hematopoietic cells suppresses macrophage apoptosis and increases atherosclerosis in low-density lipoprotein receptor null mice
    (Lippincott Williams and Wilkins, 2016) Babaev, V. R.; Yeung, M.; Erbay, E.; Ding, L.; Zhang, Y.; May, J. M.; Fazio, S.; Hotamisligil, G. S.; Linton, M. F.
    Objective - The c-Jun NH 2 -terminal kinases (JNK) are regulated by a wide variety of cellular stresses and have been implicated in apoptotic signaling. Macrophages express 2 JNK isoforms, JNK1 and JNK2, which may have different effects on cell survival and atherosclerosis. Approach and Results - To dissect the effect of macrophage JNK1 and JNK2 on early atherosclerosis, Ldlr-/- mice were reconstituted with wild-type, Jnk1-/-, and Jnk2-/- hematopoietic cells and fed a high cholesterol diet. Jnk1-/- →Ldlr-/- mice have larger atherosclerotic lesions with more macrophages and fewer apoptotic cells than mice transplanted with wild-type or Jnk2-/- cells. Moreover, genetic ablation of JNK to a single allele (Jnk1+/- /Jnk2-/- or Jnk1-/- /Jnk2+/-) in marrow of Ldlr-/- recipients further increased atherosclerosis compared with Jnk1-/- →Ldlr-/- and wild-type→Ldlr-/- mice. In mouse macrophages, anisomycin-mediated JNK signaling antagonized Akt activity, and loss of Jnk1 gene obliterated this effect. Similarly, pharmacological inhibition of JNK1, but not JNK2, markedly reduced the antagonizing effect of JNK on Akt activity. Prolonged JNK signaling in the setting of endoplasmic reticulum stress gradually extinguished Akt and Bad activity in wild-type cells with markedly less effects in Jnk1-/- macrophages, which were also more resistant to apoptosis. Consequently, anisomycin increased and JNK1 inhibitors suppressed endoplasmic reticulum stress-mediated apoptosis in macrophages. We also found that genetic and pharmacological inhibition of phosphatase and tensin homolog abolished the JNK-mediated effects on Akt activity, indicating that phosphatase and tensin homolog mediates crosstalk between these pathways. Conclusions - Loss of Jnk1, but not Jnk2, in macrophages protects them from apoptosis, increasing cell survival, and this accelerates early atherosclerosis.
  • Thumbnail Image
    ItemOpen Access
    The prosurvival IKK-related kinase IKKϵ integrates LPS and IL17A signaling cascades to promote Wnt-dependent tumor development in the intestine
    (American Association for Cancer Research, 2016-05) Göktuna, S. I.; Shostak, K.; Chau, T.-L.; Heukamp, L.C.; Hennuy, B.; Duong, H.-Q.; Ladang, A.; Close, P.; Klevernic, I.; Olivier, F.; Florin, A.; Ehx, G.; Baron, F.; Vandereyken, M.; Rahmouni, S.; Vereecke, L.; Loo, G. V.; Büttner, R.; Greten, F. R.; Chariot, A.
    Constitutive Wnt signaling promotes intestinal cell proliferation, but signals from the tumor microenvironment are also required to support cancer development. The role that signaling proteins play to establish a tumor microenvironment has not been extensively studied. Therefore, we assessed the role of the proinflammatory Ikk-related kinase Ikkϵ in Wnt-driven tumor development. We found that Ikkϵ was activated in intestinal tumors forming upon loss of the tumor suppressor Apc. Genetic ablation of Ikkϵ in b-catenin-driven models of intestinal cancer reduced tumor incidence and consequently extended survival. Mechanistically, we attributed the tumor-promoting effects of Ikkϵ to limited TNF-dependent apoptosis in transformed intestinal epithelial cells. In addition, Ikkϵ was also required for lipopolysaccharide (LPS) and IL17A-induced activation of Akt, Mek1/2, Erk1/2, and Msk1. Accordingly, genes encoding proinflammatory cytokines, chemokines, and anti-microbial peptides were downregulated in Ikkϵ-deficient tissues, subsequently affecting the recruitment of tumor-associated macrophages and IL17A synthesis. Further studies revealed that IL17A synergized with commensal bacteria to trigger Ikkϵ phosphorylation in transformed intestinal epithelial cells, establishing a positive feedback loop to support tumor development. Therefore, TNF, LPS, and IL17A-dependent signaling pathways converge on Ikkϵ to promote cell survival and to establish an inflammatory tumor microenvironment in the intestine upon constitutive Wnt activation.