title: Epithelial NEMO/IKKγ limits fibrosis and promotes regeneration during pancreatitis.
abstract: Inhibitory κB kinase (IKK)/nuclear factor κB (NF-κB) signalling has been implicated in the pathogenesis of pancreatitis, but its precise function has remained controversial. Here, we analyse the contribution of IKK/NF-κB signalling in epithelial cells to the pathogenesis of pancreatitis by targeting the IKK subunit NF-κB essential modulator (NEMO) (IKKγ), which is essential for canonical NF-κB activation.
  
  
  
  Mice with a targeted deletion of NEMO in the pancreas were subjected to caerulein pancreatitis. Pancreata were examined at several time points and analysed for inflammation, fibrosis, cell death, cell proliferation, as well as cellular differentiation. Human samples were used to corroborate findings established in mice.
  
  
  
  In acute pancreatitis, NEMO deletion in the pancreatic parenchyma resulted in minor changes during the early phase but led to the persistence of inflammatory and fibrotic foci in the recovery phase. In chronic pancreatitis, NEMO deletion aggravated inflammation and fibrosis, inhibited compensatory acinar cell proliferation, and enhanced acinar atrophy and acinar-ductal metaplasia. Gene expression analysis revealed sustained activation of profibrogenic genes and the CXCL12/CXCR4 axis in the absence of epithelial NEMO. In human chronic pancreatitis samples, the CXCL12/CXCR4 axis was activated as well, with CXCR4 expression correlating with the degree of fibrosis. The aggravating effects of NEMO deletion were attenuated by the administration of the CXCR4 antagonist AMD3100.
  
  
  
  Our results suggest that NEMO in epithelial cells exerts a protective effect during pancreatitis by limiting inflammation and fibrosis and improving acinar cell regeneration. The CXCL12/CXCR4 axis is an important mediator of that effect and may also be of importance in human chronic pancreatitis.
authors.affiliation: Institute of Physiological Chemistry, University of Ulm, Ulm, Germany.
authors.forename: Lap Kwan
authors.initials: LK
authors.lastname: Chan
authors.affiliation: Institute of Physiological Chemistry, University of Ulm, Ulm, Germany.
authors.forename: Melanie
authors.initials: M
authors.lastname: Gerstenlauer
authors.affiliation: Institute of Pathology, Technical University of Munich (TUM), Munich, Germany.
authors.forename: Björn
authors.initials: B
authors.lastname: Konukiewitz
authors.affiliation: Institute of Pathology, Technical University of Munich (TUM), Munich, Germany.
authors.forename: Katja
authors.initials: K
authors.lastname: Steiger
authors.affiliation: Institute of Pathology, Technical University of Munich (TUM), Munich, Germany.
authors.forename: Wilko
authors.initials: W
authors.lastname: Weichert
authors.affiliation: Institute of Physiological Chemistry, University of Ulm, Ulm, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Wirth
authors.affiliation: Institute of Physiological Chemistry, University of Ulm, Ulm, Germany.
authors.forename: Harald Jakob
authors.initials: HJ
authors.lastname: Maier
mesh_terms: D000208:Acute Disease; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002108:Ceruletide; D054377:Chemokine CXCL12 / Q000378:metabolism; D002908:Chronic Disease; D018450:Disease Progression; D004847:Epithelial Cells / Q000378:metabolism*; D005355:Fibrosis / Q000378:metabolism / Q000503:physiopathology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000172:deficiency / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism*; D010179:Pancreas / Q000378:metabolism / Q000473:pathology* / Q000502:physiology / Q000503:physiopathology; D010195:Pancreatitis / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology*; D019718:Receptors, CXCR4 / Q000378:metabolism; D012038:Regeneration / Q000502:physiology*
chemical_list: D015415:Biomarkers; C515255:CXCL12 protein, human; C527276:CXCR4 protein, human; C514936:CXCR4 protein, mouse; D054377:Chemokine CXCL12; C515256:Cxcl12 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; C514981:NEMO protein, mouse; D016328:NF-kappa B; D019718:Receptors, CXCR4; D002108:Ceruletide
keywords: CHEMOKINES; EXPERIMENTAL PANCREATITIS; FIBROSIS; INFLAMMATION; NUCLEAR FACTOR KAPPA B