Macrophage Migration Inhibitory Factor in Acute Adipose Tissue Inflammation.
Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine and has been implicated in inflammatory diseases. However, little is known about the regulation of MIF in adipose tissue and its impact on wound healing. The aim of this study was to investigate MIF expression in inflamed adipose and determine its role in inflammatory cell recruitment and wound healing. Adipose tissue was harvested from subcutaneous adipose tissue layers of 24 healthy subjects and from adipose tissue adjacent to acutely inflamed wounds of 21 patients undergoing wound debridement. MIF protein and mRNA expression were measured by ELISA and RT-PCR. Cell-specific MIF expression was visualized by immunohistochemistry. The functional role of MIF in cell recruitment was investigated by a chemotaxis assay and by flow cytometry of labeled macrophages that were injected into Mif-/-and wildtype mice. Wound healing was evaluated by an in vitro scratch assay on human fibroblast monolayers. MIF protein levels of native adipose tissue and supernatants from acutely inflamed wounds were significantly elevated when compared to healthy controls. MIF mRNA expression was increased in acutely inflamed adipose tissue indicating the activation of MIF gene transcription in response to adipose tissue inflammation. MIF is expressed in mature adipocytes and in infiltrated macrophages. Peripheral blood mononuclear cell migration was significantly increased towards supernatants derived from inflamed adipose tissue. This effect was partially abrogated by MIF-neutralizing antibodies. Moreover, when compared to wildtype mice, Mif-/-mice showed reduced infiltration of labeled macrophages into LPS-stimulated epididymal fat pads in vivo. Finally, MIF antibodies partially neutralized the detrimental effect of MIF on fibroblast wound healing. Our results indicate that increased MIF expression and rapid activation of the MIF gene in fat tissue adjacent to acute wound healing disorders may play a role in cell recruitment to the site of inflammation and wound healing.
Department of Plastic and Reconstructive Surgery, Hand Surgery-Burn Center, Medical Faculty, RWTH Aachen University, Aachen, Germany; Department of Medicine, Yale University School of Medicine, New Haven, Connecticut, United States of America; Institute of Biochemistry and Molecular Cell Biology, RWTH Aachen University, Aachen, Germany.
Bong-Sung
BS
Kim
Department of Plastic and Reconstructive Surgery, Hand Surgery-Burn Center, Medical Faculty, RWTH Aachen University, Aachen, Germany.
Robert
R
Rongisch
Department of Plastic and Reconstructive Surgery, Hand Surgery-Burn Center, Medical Faculty, RWTH Aachen University, Aachen, Germany.
Stephan
S
Hager
Department of Plastic and Reconstructive Surgery, Hand Surgery-Burn Center, Medical Faculty, RWTH Aachen University, Aachen, Germany.
Gerrit
G
Grieb
Department of Plastic and Reconstructive Surgery, Hand Surgery-Burn Center, Medical Faculty, RWTH Aachen University, Aachen, Germany.
Mahtab
M
Nourbakhsh
Department of Plastic and Reconstructive Surgery, Hand Surgery-Burn Center, Medical Faculty, RWTH Aachen University, Aachen, Germany.
Hans-Oliver
HO
Rennekampff
Department of Medicine, Yale University School of Medicine, New Haven, Connecticut, United States of America.
Richard
R
Bucala
Institute of Biochemistry and Molecular Cell Biology, RWTH Aachen University, Aachen, Germany.
Juergen
J
Bernhagen
Department of Plastic and Reconstructive Surgery, Hand Surgery-Burn Center, Medical Faculty, RWTH Aachen University, Aachen, Germany.
Norbert
N
Pallua
D017667:Adipocytes / Q000378:metabolism / Q000473:pathology; D000273:Adipose Tissue / Q000378:metabolism* / Q000473:pathology; D000328:Adult; D000368:Aged; D000818:Animals; D002465:Cell Movement / Q000235:genetics*; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D007249:Inflammation / Q000235:genetics* / Q000473:pathology; D019746:Intramolecular Oxidoreductases / Q000096:biosynthesis* / Q000235:genetics; D007963:Leukocytes, Mononuclear / Q000378:metabolism / Q000473:pathology; D008263:Macrophage Migration-Inhibitory Factors / Q000096:biosynthesis* / Q000235:genetics; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D012333:RNA, Messenger / Q000096:biosynthesis; D014945:Wound Healing / Q000235:genetics
D008263:Macrophage Migration-Inhibitory Factors; D012333:RNA, Messenger; D019746:Intramolecular Oxidoreductases; C515598:MIF protein, human