GDF-15 inhibits integrin activation and mouse neutrophil recruitment through the ALK-5/TGF-βRII heterodimer
作者： Annette Artz , Stefan Butz , Dietmar Vestweber
DOI: 10.1182/BLOOD-2016-01-696617
关键词:
摘要: Growth differentiation factor 15 (GDF-15) is the first cytokine known to counteract chemokine-induced activation of leukocyte integrins. We showed recently that this activity dampens neutrophil recruitment into inflamed tissue and required for survival myocardial infarction in mice. The receptor responsible GDF-15-triggered anti-inflammatory mechanism on myeloid cells not known. Here, we identify as transforming growth β I (TGF-βRI) (activin receptor-like kinase 5 [ALK-5]) TGF-β II (TGF-βRII). show interference with these receptors by small-molecule inhibitors, antibodies, or small interfering RNA, blocked GDF-15 effect integrin activation. Likewise, gene inactivation each 2 neutrophils isolated from conditional gene-deficient mice abolished inhibitory CXCL1-induced β2-integrin diapedesis. Rapid arrest induced CXCL1 vivo was inhibited an ALK-5 TGF-βRII dependent way. As mice, found extravasation deficient strongly increased interleukin-1β cremaster. effects were also TGF-β1. Mechanistically, TGF-β1 interfered inhibiting Ras-related protein 1 (Rap-1), depended CalDAG- guanine nucleotide exchange (GEF1) cell division control 42 homolog. conclude both via ALK-5/TGF-βRII heterodimer. This represents a novel, rapid
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