title: Mfge8 suppresses airway hyperresponsiveness in asthma by regulating smooth muscle contraction.
abstract: Airway obstruction is a hallmark of allergic asthma and is caused primarily by airway smooth muscle (ASM) hypercontractility. Airway inflammation leads to the release of cytokines that enhance ASM contraction by increasing ras homolog gene family, member A (RhoA) activity. The protective mechanisms that prevent or attenuate the increase in RhoA activity have not been well studied. Here, we report that mice lacking the gene that encodes the protein Milk Fat Globule-EGF factor 8 (Mfge8(-/-)) develop exaggerated airway hyperresponsiveness in experimental models of asthma. Mfge8(-/-) ASM had enhanced contraction after treatment with IL-13, IL-17A, or TNF-α. Recombinant Mfge8 reduced contraction in murine and human ASM treated with IL-13. Mfge8 inhibited IL-13-induced NF-κB activation and induction of RhoA. Mfge8 also inhibited rapid activation of RhoA, an effect that was eliminated by an inactivating point mutation in the RGD integrin-binding site in recombinant Mfge8. Human subjects with asthma had decreased Mfge8 expression in airway biopsies compared with healthy controls. These data indicate that Mfge8 binding to integrin receptors on ASM opposes the effect of allergic inflammation on RhoA activity and identify a pathway for specific inhibition of ASM hypercontractility in asthma.
authors.affiliation: Lung Biology Center, University of California, San Francisco, CA 94143, USA.
authors.forename: Makoto
authors.initials: M
authors.lastname: Kudo
authors.forename: S M Amin
authors.initials: SM
authors.lastname: Khalifeh Soltani
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Sakuma
authors.forename: William
authors.initials: W
authors.lastname: McKleroy
authors.forename: Ting-Hein
authors.initials: TH
authors.lastname: Lee
authors.forename: Prescott G
authors.initials: PG
authors.lastname: Woodruff
authors.forename: Jae Woo
authors.initials: JW
authors.lastname: Lee
authors.forename: Katherine
authors.initials: K
authors.lastname: Huang
authors.forename: Chun
authors.initials: C
authors.lastname: Chen
authors.forename: Mehrdad
authors.initials: M
authors.lastname: Arjomandi
authors.forename: Xiaozhu
authors.initials: X
authors.lastname: Huang
authors.forename: Kamran
authors.initials: K
authors.lastname: Atabai
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000954:Antigens, Surface / Q000235:genetics / Q000378:metabolism*; D001249:Asthma / Q000503:physiopathology*; D015153:Blotting, Western; D016535:Bronchial Hyperreactivity / Q000503:physiopathology*; D018893:Bronchoalveolar Lavage; D002118:Calcium / Q000378:metabolism; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006801:Humans; D018793:Interleukin-13 / Q000494:pharmacology; D008168:Lung / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D008894:Milk Proteins / Q000235:genetics / Q000378:metabolism*; D009119:Muscle Contraction / Q000502:physiology*; D009130:Muscle, Smooth / Q000502:physiology*; D016328:NF-kappa B / Q000378:metabolism; D017354:Point Mutation / Q000235:genetics; D020741:rho GTP-Binding Proteins / Q000378:metabolism; D020742:rhoA GTP-Binding Protein
chemical_list: D000954:Antigens, Surface; D018793:Interleukin-13; C490919:Mfge8 protein, mouse; D008894:Milk Proteins; D016328:NF-kappa B; C526380:RhoA protein, mouse; D020741:rho GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein; D002118:Calcium