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1 Center for Perinatal Research, Columbus Children's Research Institute, Columbus, Ohio, United States
2 Center for Gene Therapy, Columbus Children's Research Institute, Columbus, Ohio, United States
3 Pediatrics, University of Tennessee Health Sciences Center at Memphis, Memphis, Tennessee, United States
* To whom correspondence should be addressed. E-mail: NelinL{at}ccri.net.
L-arginine (L-arg) is metabolized to nitric oxide (NO) by inducible NO synthase (iNOS), or to urea and L-ornithine (L-orn) by arginase. NO is involved in the inflammatory response while arginase is the first step in polyamine and proline synthesis necessary for tissue repair and wound healing. Mitogen-activated protein kinases (MAPK) mediate LPS-induced iNOS expression, and MAPK phosphatase-1 (MKP-1) plays a crucial role in limiting MAPK signaling in macrophages. We hypothesized that MKP-1, by attenuating iNOS expression, acts as a switch changing L-arg metabolism from NO production to L-orn production after endotoxin administration. To test this hypothesis we performed studies in RAW264.7 macrophages stably transfected with an MKP-1 expression vector, in thioglyollate-elicited peritoneal macrophages harvested from wild-type and Mkp-1-/- mice, as well as in vivo in wild-type and Mkp-1-/- mice. We found that overexpression of MKP-1 resulted in lower iNOS expression and NO production, but greater urea production in response to LPS. While deficiency of MKP-1, resulted in greater iNOS expression, NO production and lower urea production in response to LPS, neither the overexpression nor the deficiency of MKP-1 had any substantial effect on the expression of the arginases.
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