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Title: EFFECT OF CIS-UROCANIC ACID ON BOVINE NEUTROPHIL GENERATION OF REACTIVE OXYGEN SPECIES

Author
item RINALDI, MANUELA - UNIVERSITY OF MILAN
item MOROIN, PAOLO - UNIVERSITY OF MILAN
item LEINO, LASSE - BIOCIS PHARMA, LTD
item Paape, Max
item Bannerman, Douglas

Submitted to: Journal of Dairy Science
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 4/25/2006
Publication Date: 11/1/2006
Citation: Rinaldi, M., Moroin, P., Leino, L., Paape, M.J., Bannerman, D.D. 2006. Effect of cis-urocanic acid on bovine neutrophil generation of reactive oxygen species. Journal of Dairy Science. 89(11):4188-4201.

Interpretive Summary: Neutrophils play a critical role in the host innate immune response during mastitis and other bacterial-mediated diseases of cattle through their ability to engulf and kill bacteria. The bactericidal activity of neutrophils is dependent upon intracellular generation of reactive oxygen species; however, extracellular production of reactive oxygen species results in tissue injury to the animal. The findings of the current study suggest that the compound cis-urocanic acid may have therapeutic applicability to limiting the production of extracellular reactive oxygen species that are damaging to host tissue while preserving neutrophil activity critical to bacterial clearance.

Technical Abstract: Neutrophils (PMN's) play a fundamental role in the host innate immune response during mastitis and other bacterial-mediated diseases of cattle. One of the critical mechanisms by which PMN's contribute to host innate immune defenses is through their ability to phagocytose and kill bacteria. The ability of PMN's to kill bacteria is mediated through the generation of reactive oxygen species (ROS). However, the extracellular release of ROS can be deleterious to the host as they elicit tissue injury. Thus, in diseases such as mastitis that are accompanied by a large influx of PMN's, the generation of large quantities of ROS by activated PMN's may result in significant injury to the mammary epithelium. Cis-urocanic acid (cis-UCA), which is formed from the UV photoisomerization of the trans isoform found naturally in human and animal skin, is an immunosuppressive molecule with anti-inflammatory properties. There is little known about the effect of cis-UCA on PMN's, although one report demonstrated that it inhibits human PMN respiratory burst activity. However, the nature of this inhibition remains unknown. Because of the potential therapeutic use that a molecule such as cis-UCA may have in blocking excessive respiratory burst activity that may be deleterious to the host, the ability of cis-UCA to inhibit bovine PMN production of ROS was studied. Further, since PMN generation of ROS is necessary for optimal PMN bactericidal activity, which is critical for host innate immune defenses against infection, the effect of cis-UCA on bovine PMN phagocytosis and bacterial killing were assayed. Cis-UCA dose-dependently inhibited the respiratory burst activity of bovine PMN's as measured by luminol chemiluminescence. Subsequently, the effect of cis-UCA on the production of specific oxygen radicals using more selective assays was investigated. Using two distinct assays, it was established that cis-UCA inhibits the generation of extracellular superoxide. In contrast, cis-UCA had no effect on the generation of intracellular levels of superoxide or other ROS. At concentrations that inhibited generation of extracellular superoxide, bovine PMN phagocytosis and bacterial activity remained intact. Together, these data suggest that cis-UCA inhibits the tissue-damaging generation of extracellular ROS while preserving PMN bactericidal activity.