title: Therapeutic Role of Interleukin 22 in Experimental Intra-abdominal Klebsiella pneumoniae Infection in Mice.
abstract: Interleukin 22 (IL-22) is an IL-10-related cytokine produced by T helper 17 (Th17) cells and other immune cells that signals via IL-22 receptor alpha 1 (IL-22Ra1), which is expressed on epithelial tissues, as well as hepatocytes. IL-22 has been shown to have hepatoprotective effects that are mediated by signal transducer and activator of transcription 3 (STAT3) signaling. However, it is unclear whether IL-22 can directly regulate antimicrobial programs in the liver. To test this hypothesis, hepatocyte-specific IL-22Ra1 knockout (Il22Ra1(Hep-/-)) and Stat3 knockout (Stat3(Hep-/-)) mice were generated and subjected to intra-abdominal infection with Klebsiella pneumoniae, which results in liver injury and necrosis. We found that overexpression of IL-22 or therapeutic administration of recombinant IL-22 (rIL-22), given 2 h postinfection, significantly reduced the bacterial burden in both the liver and spleen. The antimicrobial activity of rIL-22 required hepatic Il22Ra1 and Stat3. Serum from rIL-22-treated mice showed potent bacteriostatic activity against K. pneumoniae, which was dependent on lipocalin 2 (LCN2). However, in vivo, rIL-22-induced antimicrobial activity was only partially reduced in LCN2-deficient mice. We found that rIL-22 also induced serum amyloid A2 (SAA2) and that SAA2 had anti-K. pneumoniae bactericidal activity in vitro. These results demonstrate that IL-22, through IL-22Ra1 and STAT3 singling, can induce intrinsic antimicrobial activity in the liver, which is due in part to LCN2 and SAA2. Therefore, IL-22 may be a useful adjunct in treating hepatic and intra-abdominal infections.
authors.affiliation: R. K. Mellon Foundation Institute for Pediatric Research, Children's Hospital of Pittsburgh of UPMC, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Mingquan
authors.initials: M
authors.lastname: Zheng
authors.affiliation: R. K. Mellon Foundation Institute for Pediatric Research, Children's Hospital of Pittsburgh of UPMC, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: William
authors.initials: W
authors.lastname: Horne
authors.affiliation: R. K. Mellon Foundation Institute for Pediatric Research, Children's Hospital of Pittsburgh of UPMC, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Jeremy P
authors.initials: JP
authors.lastname: McAleer
authors.affiliation: Tulane University, School of Medicine, Section of Pulmonary Diseases Critical Care and Environmental Medicine, New Orleans, Louisiana, USA.
authors.forename: Derek
authors.initials: D
authors.lastname: Pociask
authors.affiliation: R. K. Mellon Foundation Institute for Pediatric Research, Children's Hospital of Pittsburgh of UPMC, University of Pittsburgh, Pittsburgh, Pennsylvania, USA University of Pittsburgh School of Medicine, Department of Immunology, Pittsburgh, Pennsylvania, USA.
authors.forename: Taylor
authors.initials: T
authors.lastname: Eddens
authors.affiliation: R. K. Mellon Foundation Institute for Pediatric Research, Children's Hospital of Pittsburgh of UPMC, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Misty
authors.initials: M
authors.lastname: Good
authors.affiliation: Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Bin
authors.initials: B
authors.lastname: Gao
authors.affiliation: R. K. Mellon Foundation Institute for Pediatric Research, Children's Hospital of Pittsburgh of UPMC, University of Pittsburgh, Pittsburgh, Pennsylvania, USA jay.kolls@chp.edu.
authors.forename: Jay K
authors.initials: JK
authors.lastname: Kolls
mesh_terms: D000818:Animals; D005260:Female; D006801:Humans; D007378:Interleukins / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism*; D059413:Intraabdominal Infections / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000382:microbiology; D007710:Klebsiella Infections / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000382:microbiology; D007711:Klebsiella pneumoniae / Q000235:genetics / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018123:Receptors, Interleukin / Q000235:genetics / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D000097043:Interleukin-22
chemical_list: D007378:Interleukins; D018123:Receptors, Interleukin; D050796:STAT3 Transcription Factor; D000097043:Interleukin-22; C415369:interleukin-22 receptor