title: Decrease in IL-10 and increase in TNF-α levels in renal tissues during systemic inhibition of nitric oxide in anesthetized mice.
abstract: Earlier, we demonstrated that the inhibition of nitric oxide synthase (NOS) by nitro-l-arginine methyl ester (l-NAME) infusion increases the endogenous production of proinflammatory cytokine, tumor necrosis factor (TNF-α). In the present study, we examined the hypothesis that inhibition of nitric oxide (NO) production leads to the suppression of interleukin (IL)-10 (anti-inflammatory cytokine) generation which facilitates the enhancement of TNF-α production endogenously. Using appropriate enzyme-linked immunosorbent assay kits and immunohistochemical staining, the levels of IL-10 and TNF-α in plasma (P) and in renal tissues (R) were measured in anesthetized mice (C57BL/6; ~10 weeks age; n = 6/group) infused with or without l-NAME (200 μg/min/kg; i.v. for 2 h). Compared to vehicle-treated control mice, l-NAME-treated mice had a lower level of IL-10 (P, 0.3 ± 0.1 vs. 2.6 ± 0.6 ng/mL; R, 0.5 ± 0.1 vs. 3 ± 0.1 ng/mg protein) and a higher level of TNF-α (P, 432 ± 82 vs. undetected pg/mL; R, 58 ± 7 vs. 6 ± 5 pg/mg protein). IL-10 protein expression, present mostly in the distal nephron segments in control mice, was markedly downregulated in l-NAME-treated mice. Compared to control mice, TNF-α expression increased 2.5-fold in renal cortical sections (mostly in the distal nephron segments) in l-NAME-treated mice. Coinfusion of a NO donor, S-nitroso-N-acetyl-penicillamine (SNAP; 25 μg/min/kg) with l-NAME in a separate group of mice prevented these changes in IL-10 and TNF-α induced by l-NAME. IL-10 infusion (0.075 ng/min/g) in l-NAME-treated mice markedly attenuated l-NAME-induced increments in TNF-α. Thus, these results demonstrate that NOS inhibition decreases endogenous IL-10 generation and thus, minimizes its immune downregulating action on the TNF-α production in the kidney.
authors.affiliation: Department of Physiology, Hypertension & Renal Center of Excellence, Tulane University Health Sciences Center, New Orleans, 70112, Louisiana.
authors.forename: Purnima
authors.initials: P
authors.lastname: Singh
authors.affiliation: Department of Physiology, Hypertension & Renal Center of Excellence, Tulane University Health Sciences Center, New Orleans, 70112, Louisiana.
authors.forename: Alexander
authors.initials: A
authors.lastname: Castillo
authors.affiliation: Department of Physiology, Hypertension & Renal Center of Excellence, Tulane University Health Sciences Center, New Orleans, 70112, Louisiana.
authors.forename: Dewan S A
authors.initials: DS
authors.lastname: Majid
keywords: IL‐10; SNAP; TNF‐α; kidney; l‐NAME; nitric oxide synthase
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