Alterations in nitric oxide and cytokine production with airway inflammation in the absence of IL-10

IL-10 is an anti-inflammatory cytokine that suppresses NO synthase (NOS) and production of NO; its lack may promote NO production and alterations in cytokines modulated by NO with allergic airway inflammation (AI), such as IL-18 and IL-4. Therefore, we induced AI in IL-10 knockout (^-/-) and IL-10-sufficient C57BL/6 (C57) mice with inhaled OVA and measured airway NO production, as exhaled NO (E_NO) and bronchoalveolar lavage fluid nitrite levels. E_NO and nitrite levels were elevated significantly in naive IL-10^-/- mice as compared with C57 mice. With AI, E _NO and nitrite levels increased in C57 mice and decreased in IL-10^-/- mice. IL-18 production fell with both AI and addition of S-nitroso-N-acetyl-D,L-penicillamine (a NO donor) but was not significantly increased by chemical NOS inhibition by L-N⁵-(1-iminoethyl)- ornithine. IL-4 AI was increased significantly (up to 10-fold greater) in the absence of IL-10 but was reduced significantly with chemical inhibition of NOS. Airway responsiveness was lower in IL-10^-/- mice and was associated with alteration in production of NO and IL-4. Thus, IL-4 production was increased, and likely decreased NO production, in a way not predicted by the absence of IL-10. Inhibition of IL-4 production, with inhibition of NOS in the absence of IL-10, demonstrated the importance of a NO and IL-4 feedback mechanism regulating this interaction.