Down-Regulation of Inducible Nitric-Oxide Synthase (NOS-2) During Parasite-Induced Gut Inflammation: A Path to Identify a Selective NOS-2 Inhibitor
- Department of Integrative Biology and Pharmacology and the Institute of Molecular Medicine, The University of Texas-Houston Medical School, Houston, Texas
Abstract
Nitric oxide (NO) possesses potent anti-inflammatory properties; however, an over-production of NO will promote inflammation and induce cell and tissue dysfunction. Thus, the ability to precisely regulate NO production could prove beneficial in controlling damage. In this study, advantage was taken of the well characterized inflammatory response caused by an intestinal parasite, Trichinella spiralis, to study the relationship between intestinal inflammation and the regulation of nitric oxide synthase-type 2 (NOS-2) expression. Our study revealed that a specific gut inflammatory reaction results in inhibition of NOS-2 expression. Characteristics of this inhibition are: 1) local jejunal inflammation induced by T. spiralissystemically inhibits NOS-2 gene transcription, protein expression, and enzyme activity; 2) the inhibition blunts endotoxin-stimulated NOS-2 expression; 3) the inhibition does not extend to the expression of other isoforms of NOS, to paxillin, a housekeeper protein, or to cyclooxygenase-2, another protein induced by proinflammatory cytokines; 4) the inhibition is unlikely related to the formation of specific anti-parasite antibodies; and 5) the inhibition may involve substances other than stress-induced corticosteroids. Elucidation of such potent endogenous NOS-2 down-regulatory mechanisms could lead to the development of new strategies for the therapy of inflammatory conditions characterized by the overproduction of NO.
Footnotes
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Send reprint requests to: Dr. Ferid Murad, Department of Integrative Biology, Physiology, and Pharmacology, The University of Texas-Houston Medical School, 6431 Fannin St., MSB 4.000, Houston, TX 77030-0708. E-mail: fmurad{at}girch1.med.uth.tmc.edu
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Financial support was partially provided by the John S. Dunn, G. Harold and Leila Mathers, and Robert A. Welch Foundations as well as The University of Texas.
- Abbreviations:
- NO
- nitric oxide
- NOS
- NO synthase
- COX-2
- cyclooxygenase-2
- LPS
- lipopolysaccharide
- ONOO
- peroxynitrite
- MPO
- myeloperoxidase
- PAGE
- polyacrylamide gel electrophoresis
- PCR
- polymerase chain reaction
- Q-PCR
- quantitative-PCR
- RT-PCR
- reverse transcriptase-PCR
- GAPDH
- glyceraldehyde-3-phosphate dehydrogenase
- IL
- interleukin
- IFN
- interferon
- FAM
- carboxyfluorescein
- TAMRA
- carboxytetramethylthrolamine
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- Received September 21, 2000.
- Accepted January 5, 2001.
- The American Society for Pharmacology and Experimental Therapeutics
