Linomide administration to mice attenuates the induction of nitric oxide synthase elicited by lipopolysaccharide-activated macrophages and prevents nephritis in MRL/Mp-lpr/lpr mice.
Nitric oxide is involved as a messenger molecule in a large number of physiologic and pathologic responses. Local generation of high nitric oxide output through the expression of the calcium-independent, cytokine-inducible form of nitric oxide synthase (iNOS) can result in either protective or damaging effects. The development of drugs that specifically suppress iNOS expression or inhibit its activity may therefore provide an excellent therapeutic tool for treatment of a diverse set of dysfunctions, including asthma, inflammatory processes, and autoimmune disease. We show compelling evidence that linomide, an immunomodulator known to ameliorate autoimmune diseases, prevents accumulation in the macrophages of mRNA encoding iNOS in mice injected with LPS. This effect is partially mediated by the blocking of TNF-alpha and IL-beta production by activated macrophages. Here, we also present evidence that kidneys from MRL/Mp-lpr/lpr mice express high iNOS levels when the mice develop glomerulonephritis. The administration of linomide to MRL/Mp-lpr/lpr mice significantly decreases iNOS mRNA levels and prevents the development of glomerulonephritis, extending the half-life of mice of this strain. This linomide effect is compatible with its role in preventing the development of autoimmune disease and extends its possible use to other pathologic manifestations associated with iNOS expression, such as the systemic lupus erythematosus-associated glomerulonephritis present in MRL/Mp-lpr/lpr mice.
Hortelano
S
S
Department of Biochemistry, Complutense University, Madrid, Spain.
Díaz-Guerra
M J
MJ
Gonzalez-García
A
A
Leonardo
E
E
Gamallo
C
C
Boscá
L
L
Martínez-A
C
C
D000276:Adjuvants, Immunologic; D000818:Animals; D004790:Enzyme Induction / Q000187:drug effects; D006912:Hydroxyquinolines / Q000494:pharmacology*; D007668:Kidney / Q000201:enzymology / Q000473:pathology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008180:Lupus Erythematosus, Systemic / Q000188:drug therapy / Q000473:pathology; D008262:Macrophage Activation; D051379:Mice; D019463:Mice, Inbred MRL lpr / Q000276:immunology; D009393:Nephritis / Q000517:prevention & control*; D019001:Nitric Oxide Synthase / Q000096:biosynthesis*; D012772:Shock, Septic / Q000201:enzymology
D000276:Adjuvants, Immunologic; D006912:Hydroxyquinolines; D008070:Lipopolysaccharides; C045282:roquinimex; D019001:Nitric Oxide Synthase