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The journal of immunology : official journal of the American Association of Immunologists v.197 no.7, 2016년, pp.2909 - 2917   SCI SCIE
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Lactic Acid Suppresses IL-33–Mediated Mast Cell Inflammatory Responses via Hypoxia-Inducible Factor-1α–Dependent miR-155 Suppression

Abebayehu, Daniel (Department of Biomedical Engineering, Virginia Commonwealth University, Richmond, VA 23284 ) ; Spence, Andrew J. (Department of Biology, Virginia Commonwealth University, Richmond, VA 23284 ) ; Qayum, Amina Abdul (Department of Biology, Virginia Commonwealth University, Richmond, VA 23284 ) ; Taruselli, Marcela T. (Department of Biology, Virginia Commonwealth University, Richmond, VA 23284 ) ; McLeod, Jamie J. A. (Department of Biology, Virginia Commonwealth University, Richmond, VA 23284 ) ; Caslin, Heather L. (Department of Biology, Virginia Commonwealth University, Richmond, VA 23284 ) ; Chumanevich, Alena P. (Department of Pathology, Microbiology, and Immunology, University of South Carolina School of Medicine, Columbia, SC 29208 ) ; Kolawole, Elizabeth Motunrayo (and ) ; Paranjape, Anuya (Department of Biology, Virginia Commonwealth University, Richmond, VA 23284 ) ; Baker, Bianca (Department of Biology, Virginia Commonwealth University, Richmond, VA 23284 ) ; Ndaw, Victor S. (Department of Biology, Virginia Commonwealth University, Richmond, VA 23284 ) ; Barnstein, Brian O. (Department of Biology, Virginia Commonwealth University, Richmond, VA 23284 ) ; Oskeritzian, Carole A. (Department of Biology, Virginia Commonwealth University, Richmond ) ; Sell, Scott A. ; Ryan, John J. ;
  • 초록  

    Lactic acid (LA) is present in tumors, asthma, and wound healing, environments with elevated IL-33 and mast cell infiltration. Although IL-33 is a potent mast cell activator, how LA affects IL-33–mediated mast cell function is unknown. To investigate this, mouse bone marrow–derived mast cells were cultured with or without LA and activated with IL-33. LA reduced IL-33–mediated cytokine and chemokine production. Using inhibitors for monocarboxylate transporters (MCT) or replacing LA with sodium lactate revealed that LA effects are MCT-1– and pH-dependent. LA selectively altered IL-33 signaling, suppressing TGF-β–activated kinase-1, JNK, ERK, and NF-κB phosphorylation, but not p38 phosphorylation. LA effects in other contexts have been linked to hypoxia-inducible factor (HIF)-1α, which was enhanced in bone marrow–derived mast cells treated with LA. Because HIF-1α has been shown to regulate the microRNA miR-155 in other systems, LA effects on miR-155-5p and miR-155-3p species were measured. In fact, LA selectively suppressed miR-155-5p in an HIF-1α–dependent manner. Moreover, overexpressing miR-155-5p, but not miR-155-3p, abolished LA effects on IL-33–induced cytokine production. These in vitro effects of reducing cytokines were consistent in vivo, because LA injected i.p. into C57BL/6 mice suppressed IL-33–induced plasma cytokine levels. Lastly, IL-33 effects on primary human mast cells were suppressed by LA in an MCT-dependent manner. Our data demonstrate that LA, present in inflammatory and malignant microenvironments, can alter mast cell behavior to suppress inflammation.


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