title: IL-6 regulates adipose deposition and homeostasis in lymphedema.
abstract: Lymphedema (LE) is a morbid disease characterized by chronic limb swelling and adipose deposition. Although it is clear that lymphatic injury is necessary for this pathology, the mechanisms that underlie lymphedema remain unknown. IL-6 is a known regulator of adipose homeostasis in obesity and has been shown to be increased in primary and secondary models of lymphedema. Therefore, the purpose of this study was to determine the role of IL-6 in adipose deposition in lymphedema. The expression of IL-6 was analyzed in clinical tissue specimens and serum from patients with or without LE, as well as in two mouse models of lymphatic injury. In addition, we analyzed IL-6 expression/adipose deposition in mice deficient in CD4(+) cells (CD4KO) or IL-6 expression (IL-6KO) or mice treated with a small molecule inhibitor of IL-6 or CD4 depleting antibodies to determine how IL-6 expression is regulated and the effect of changes in IL-6 expression on adipose deposition after lymphatic injury. Patients with LE and mice treated with lymphatic excision of the tail had significantly elevated tissue and serum expression of IL-6 and its downstream mediator. The expression of IL-6 was associated with adipose deposition and CD4(+) inflammation and was markedly decreased in CD4KO mice. Loss of IL-6 function resulted in significantly increased adipose deposition after tail lymphatic injury. Our findings suggest that IL-6 is increased as a result of adipose deposition and CD4(+) cell inflammation in lymphedema. In addition, our study suggests that IL-6 expression in lymphedema acts to limit adipose accumulation.
authors.affiliation: The Department of Surgery, Division of Plastic and Reconstructive Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York;
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Cuzzone
authors.affiliation: The Department of Surgery, Division of Plastic and Reconstructive Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York;
authors.forename: Evan S
authors.initials: ES
authors.lastname: Weitman
authors.affiliation: The Department of Surgery, Division of Plastic and Reconstructive Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York;
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Albano
authors.affiliation: The Department of Surgery, Division of Plastic and Reconstructive Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York;
authors.forename: Swapna
authors.initials: S
authors.lastname: Ghanta
authors.affiliation: The Department of Surgery, Division of Plastic and Reconstructive Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York;
authors.forename: Ira L
authors.initials: IL
authors.lastname: Savetsky
authors.affiliation: The Department of Surgery, Division of Plastic and Reconstructive Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York;
authors.forename: Jason C
authors.initials: JC
authors.lastname: Gardenier
authors.affiliation: The Department of Surgery, Division of Plastic and Reconstructive Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York;
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Joseph
authors.affiliation: The Department of Surgery, Division of Plastic and Reconstructive Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York;
authors.forename: Jeremy S
authors.initials: JS
authors.lastname: Torrisi
authors.affiliation: The Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York;
authors.forename: Jacqueline F
authors.initials: JF
authors.lastname: Bromberg
authors.affiliation: The Department of Surgical Research and Transplantology, Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland;
authors.forename: Waldemar L
authors.initials: WL
authors.lastname: Olszewski
authors.affiliation: The Department of Medicine, Division of Cardiology, Stanford University Medical Center, Stanford, California.
authors.forename: Stanley G
authors.initials: SG
authors.lastname: Rockson
authors.affiliation: The Department of Surgery, Division of Plastic and Reconstructive Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York; mehrarab@mskcc.org.
authors.forename: Babak J
authors.initials: BJ
authors.lastname: Mehrara
mesh_terms: D000273:Adipose Tissue / Q000473:pathology / Q000503:physiopathology; D050154:Adiposity / Q000502:physiology*; D000818:Animals; D001706:Biopsy; D015496:CD4-Positive T-Lymphocytes / Q000473:pathology; D016022:Case-Control Studies; D004195:Disease Models, Animal; D005260:Female; D006706:Homeostasis / Q000502:physiology*; D006801:Humans; D015850:Interleukin-6 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D008209:Lymphedema / Q000473:pathology / Q000503:physiopathology*; D008221:Lymphoid Tissue / Q000293:injuries / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout
chemical_list: D015850:Interleukin-6
keywords: IL-6; adipose; inflammation; lymphedema; serum levels