title: Autophagy is required for IL-2-mediated fibroblast growth.
abstract: Autophagy is an evolutionarily conserved pathway responsible for delivery of cytoplasmic material into the lysosomal degradation pathway to enable vesicular exocytosis. Interleukin (IL)-2 is produced by T-cells and its activity is important for immunoregulation. Fibroblasts are an immune competent cell type, playing a critical role in wound healing, chronic inflammation, and tumor development. Although autophagy plays an important role in each of these processes, whether it regulates IL-2 activity in fibroblasts is unknown. Here, we show that autophagy is required for IL-2-induced cell growth in fibroblasts. IL-2 significantly induced autophagy in mouse embryonic fibroblasts (MEFs) and primary lung fibroblasts. Autophagy inhibitors (e.g., 3-methylamphetamine and bafilomycin A1) or knockdown of ATG5 and beclin 1 blocked clinical grade IL-2-induced autophagy. Moreover, IL-2 induced HMGB1 cytoplasmic translocation in MEFs and promoted interaction between HMGB1 and beclin1, which is required for autophagy induction. Pharmacological and genetic inhibition of autophagy inhibited IL-2-induced cell proliferation and enhanced IL-2-induced apoptosis. These findings suggest that autophagy is an important pro-survival regulator for IL-2-induced cell growth in fibroblasts.
authors.affiliation: Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania 15219, USA.
authors.forename: Rui
authors.initials: R
authors.lastname: Kang
authors.forename: Daolin
authors.initials: D
authors.lastname: Tang
authors.forename: Michael T
authors.initials: MT
authors.lastname: Lotze
authors.forename: Herbert J
authors.initials: HJ
authors.lastname: Zeh Iii
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D051017:Apoptosis Regulatory Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D001343:Autophagy / Q000235:genetics / Q000502:physiology*; D000071187:Autophagy-Related Protein 5; D000071186:Beclin-1; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D004622:Embryo, Mammalian; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D055785:Gene Knockdown Techniques; D024243:HMGB1 Protein / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D007376:Interleukin-2 / Q000494:pharmacology*; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D011485:Protein Binding / Q000502:physiology; D021381:Protein Transport / Q000502:physiology; D034741:RNA, Small Interfering / Q000494:pharmacology
chemical_list: D051017:Apoptosis Regulatory Proteins; C495773:Atg5 protein, mouse; D000071187:Autophagy-Related Protein 5; D000071186:Beclin-1; C115010:Becn1 protein, mouse; D024243:HMGB1 Protein; D007376:Interleukin-2; D008869:Microtubule-Associated Proteins; D034741:RNA, Small Interfering