IL-22 induces lipopolysaccharide-binding protein in hepatocytes: a potential systemic role of IL-22 in Crohn's disease.
Crohn's disease (CD) is a common, chronic, inflammatory bowel disease characterized by intestinal infiltration of activated immune cells and distortion of the intestinal architecture. In this study, we demonstrate that IL-22, a cytokine that is mainly produced by activated Th1 and Th17 cells, was present in high quantities in the blood of CD patients in contrast to IFN-gamma and IL-17. In a mouse colitis model, IL-22 mRNA expression was elevated predominantly in the inflamed intestine but also in the mesenteric lymph nodes. IL-22BP, the soluble receptor for IL-22, demonstrated an affinity to IL-22 that was at least 4-fold higher than its membrane-bound receptor, and its strong constitutive expression in the intestine and lymph nodes was decreased in the inflamed intestine. To investigate the possible role of systemic IL-22 in CD, we then administered IL-22 to healthy mice and found an up-regulation of LPS-binding protein (LBP) blood levels reaching concentrations known to neutralize LPS. This systemic up-regulation was associated with increased hepatic but not renal or pulmonary LBP mRNA levels. IL-22 also enhanced the secretion of LBP in human primary hepatocytes and HepG2 hepatoma cells in vitro. This increase was mainly transcriptionally regulated and synergistic with that of other LBP inducers. Finally, elevated LBP levels were detected in CD patients and the mouse colitis model. These data suggest that systemic IL-22 may contribute to the prevention of systemic inflammation provoked by LPS present in the blood of CD patients through its induction of hepatic LBP.
Wolk
Kerstin
K
Interdisciplinary Group of Molecular Immunopathology, Dermatology/Medical Immunology, Campus Charité Mitte, University Hospital Charité, Charitéplatz 1, Berlin, Germany.
Witte
Ellen
E
Hoffmann
Ute
U
Doecke
Wolf-Dietrich
WD
Endesfelder
Stefanie
S
Asadullah
Khusru
K
Sterry
Wolfram
W
Volk
Hans-Dieter
HD
Wittig
Bianca Maria
BM
Sabat
Robert
R
D000209:Acute-Phase Proteins / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D003424:Crohn Disease / Q000276:immunology* / Q000473:pathology; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D007371:Interferon-gamma / Q000097:blood; D020381:Interleukin-17 / Q000097:blood; D007378:Interleukins / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D007668:Kidney / Q000276:immunology; D008070:Lipopolysaccharides / Q000276:immunology; D008099:Liver / Q000276:immunology*; D008168:Lung / Q000276:immunology; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008815:Mice, Inbred Strains; D023421:Models, Animal; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D050791:STAT Transcription Factors / Q000378:metabolism; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology; D000097043:Interleukin-22; D000099231:Lipopolysaccharide-Binding Protein
D000209:Acute-Phase Proteins; D002352:Carrier Proteins; D007371:Interferon-gamma; D020381:Interleukin-17; D007378:Interleukins; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D050791:STAT Transcription Factors; D000097043:Interleukin-22; D000099231:Lipopolysaccharide-Binding Protein