TNF-alpha-dependent regulation of acute pancreatitis severity by Ly-6C(hi) monocytes in mice.

Abstract

The roles of monocytes/macrophages and their mechanisms of action in the regulation of pancreatitis are poorly understood. To address these issues, we have employed genetically altered mouse strains that either express the human diphtheria toxin receptor (DTR) coupled to the CD11b promoter or have global deletion of TNF-α. Targeted, conditional depletion of monocytes/macrophages was achieved by administration of diphtheria toxin (DT) to CD11b-DTR mice. We show that in the absence of DT administration, pancreatitis is associated with an increase in pancreatic content of Ly-6C(hi) monocytes/macrophages but that this response is prevented by prior administration of DT to CD11b-DTR mice. DT administration also reduces pancreatic edema and acinar cell injury/necrosis in two dissimilar experimental models of acute pancreatitis (a secretagogue-induced model and a model elicited by retrograde pancreatic duct infusion of sodium taurocholate). In the secretagogue-elicited model, the DT-induced decrease in pancreatitis severity is reversed by adoptive transfer of purified Ly-6C(hi) monocytes harvested from non-DT-treated CD11b-DTR mice or by the transfer of purified Ly-6C(hi) monocytes harvested from TNF-α(+/+) donor mice, but it is not reversed by the transfer of Ly-6C(hi) monocytes harvested from TNF-α(-/-) donors. Our studies indicate that the Ly-6C(hi) monocyte subset regulates the severity of pancreatitis by promoting pancreatic edema and acinar cell injury/necrosis and that this phenomenon is dependent upon the expression of TNF-α by those cells. They suggest that therapies targeting Ly-6C(hi) monocytes and/or TNF-α expression by Ly-6C(hi) monocytes might prove beneficial in the prevention or treatment of acute pancreatitis.

• Authors: George Perides, Eric R Weiss, Emily S Michael, Johanna M Laukkarinen, Jeremy S Duffield, Michael L Steer
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 286 Issue 15 Pg. 13327-35 (Apr 15 2011) ISSN: 1083-351X [Electronic] United States
• PMID: 21343291 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Antigens, Ly
• CD11b Antigen
• Diphtheria Toxin
• HBEGF protein, human
• Hbegf protein, mouse
• Heparin-binding EGF-like Growth Factor
• ITGAM protein, human
• Intercellular Signaling Peptides and Proteins
• Ly-6C antigen, mouse
• Tumor Necrosis Factor-alpha

Topics

• Adoptive Transfer
• Animals
• Antigens, Ly (genetics, immunology, metabolism)
• CD11b Antigen (genetics, immunology, metabolism)
• Diphtheria Toxin (toxicity)
• Disease Models, Animal
• Heparin-binding EGF-like Growth Factor
• Humans
• Intercellular Signaling Peptides and Proteins (biosynthesis, genetics, immunology)
• Macrophages (immunology, metabolism, pathology)
• Mice
• Mice, Transgenic
• Monocytes (immunology, metabolism, pathology, transplantation)
• Pancreas, Exocrine (immunology, metabolism, pathology)
• Pancreatitis, Acute Necrotizing (chemically induced, genetics, immunology, metabolism, pathology)
• Severity of Illness Index
• Tumor Necrosis Factor-alpha (genetics, immunology, metabolism)