Enhanced nitric oxide production associated with airway hyporesponsiveness in the absence of IL-10

Interleukin (IL)-10 is an anti-inflammatory cytokine implicated in the regulation of airway inflammation in asthma. Among other activities, IL-10 suppresses production of nitric oxide (NO); consequently, its absence may permit increased NO production, which can affect airway smooth muscle contractility. Therefore, we investigated airway reactivity (AR) in response to methacholine (MCh) in IL-10 knockout (^-/-) mice compared with wild-type C57BL/6 (C57) mice, in which airway NO production was measured as exhaled NO (E _NO), and NO production was altered with administration of either NO synthase (NOS)-specific inhibitors or recombinant murine (rm)IL-10. AR, measured as enhanced pause in vivo, and tracheal ring tension in vitro were lower in IL-10^-/- mice by 25-50%, which was associated with elevated E _NO levels (13 vs. 7 ppb). Administration of NOS inhibitors N ^G-nitro-L-arginine methyl ester (8 mg/kg ip) or L-N ^G-(1-iminoethyl)-lysine (3 mg/kg ip) to IL-10^-/- mice decreased E_NO by an average of 50%, which was associated with increased AR, to levels similar to C57 mice. E_NO in IL-10 ^-/- mice decreased in a dose-dependent fashion in response to administered rmIL-10, to levels similar to C57 mice (7 ppb), which was associated with a 30% increment in AR. Thus increased NO production in the absence of IL-10, decreased AR, which was reversed with inhibition of NO, either by inhibition of NOS, or with reconstitution of IL-10. These findings suggest that airway NO production can modulate airway smooth muscle contractility, resulting in airway hyporesponsiveness when IL-10 is absent.