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IL-13 and IL-17A activate ß1 integrin through an NF-kB/Rho kinase/PIP5K1γ pathway to enhance force transmission in airway smooth muscle.
Ngo, Uyen; Shi, Ying; Woodruff, Prescott; Shokat, Kevan; DeGrado, William; Jo, Hyunil; Sheppard, Dean; Sundaram, Aparna B.
Afiliación
  • Ngo U; Division of Pulmonary, Critical Care, Allergy and Sleep, Department of Medicine, University of California, San Francisco, CA 94143.
  • Shi Y; Sandler Asthma Basic Research Center, University of California, San Francisco, CA 94143.
  • Woodruff P; Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA 94143.
  • Shokat K; Division of Pulmonary, Critical Care, Allergy and Sleep, Department of Medicine, University of California, San Francisco, CA 94143.
  • DeGrado W; Sandler Asthma Basic Research Center, University of California, San Francisco, CA 94143.
  • Jo H; Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA 94143.
  • Sheppard D; Howard Hughes Medical Institute, University of California, San Francisco, CA 94143.
  • Sundaram AB; Cardiovascular Research Institute, University of California, San Francisco, CA 94143.
Proc Natl Acad Sci U S A ; 121(34): e2401251121, 2024 Aug 20.
Article en En | MEDLINE | ID: mdl-39136993
ABSTRACT
Integrin activation resulting in enhanced adhesion to the extracellular matrix plays a key role in fundamental cellular processes. Although integrin activation has been extensively studied in circulating cells such as leukocytes and platelets, much less is known about the regulation and functional impact of integrin activation in adherent cells such as smooth muscle. Here, we show that two different asthmagenic cytokines, IL-13 and IL-17A, activate type I and IL-17 cytokine receptor families, respectively, to enhance adhesion of airway smooth muscle. These cytokines also induce activation of ß1 integrins detected by the conformation-specific antibody HUTS-4. Moreover, HUTS-4 binding is increased in the smooth muscle of patients with asthma compared to nonsmokers without lung disease, suggesting a disease-relevant role for integrin activation in smooth muscle. Indeed, integrin activation induced by the ß1-activating antibody TS2/16, the divalent cation manganese, or the synthetic peptide ß1-CHAMP that forces an extended-open integrin conformation dramatically enhances force transmission in smooth muscle cells and airway rings even in the absence of cytokines. We demonstrate that cytokine-induced activation of ß1 integrins is regulated by a common pathway of NF-κB-mediated induction of RhoA and its effector Rho kinase, which in turn stimulates PIP5K1γ-mediated synthesis of PIP2 at focal adhesions, resulting in ß1 integrin activation. Taken together, these data identify a pathway by which type I and IL-17 cytokine receptor family stimulation induces functionally relevant ß1 integrin activation in adherent smooth muscle and help to explain the exaggerated force transmission that characterizes chronic airway diseases such as asthma.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Asma / FN-kappa B / Interleucina-13 / Integrina beta1 / Interleucina-17 / Quinasas Asociadas a rho / Músculo Liso Límite: Animals / Humans Idioma: En Revista: Proc Natl Acad Sci U S A Año: 2024 Tipo del documento: Article Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Asma / FN-kappa B / Interleucina-13 / Integrina beta1 / Interleucina-17 / Quinasas Asociadas a rho / Músculo Liso Límite: Animals / Humans Idioma: En Revista: Proc Natl Acad Sci U S A Año: 2024 Tipo del documento: Article Pais de publicación: Estados Unidos