Alterations in Nitric Oxide and Cytokine Production with Airway Inflammation in the Absence of IL-10

Abstract

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 (ENO) and bronchoalveolar lavage fluid nitrite levels. ENO and nitrite levels were elevated significantly in naive IL-10−/− mice as compared with C57 mice. With AI, ENO 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.

IL-10 administration attenuates pulmonary neutrophil infiltration and alters pulmonary iNOS activation following hemorrhagic shock

“…This is in accordance with other studies, which showed that IL-10 alters iNOS activity and NO production. Ameredes et al showed that IL-10 deficiency decreased pulmonary NO, and observed an early inverse association of pulmonary NO and pulmonary inflammation (34). This would support our finding that IL-10 administration increased iNOS activity, thereby increased NO release and consequently decreased pulmonary neutrophil inflammation.…”

Role of IL-10 in the Resolution of Airway Inflammation

“…However, the sources of IL-10 regulation, and its specific effects and targets, have not been universally determined in animal models of airway inflammation. For example, in some studies, IL-10-deficient mice demonstrated increased eosinophilic airway inflammation with sensitization and challenge [58,59], while other studies of those mice showed decreased eosinophilic airway inflammation [60,61]. The discrepancies in these findings may be modeldependent, such that longer-term models of allergic airway inflammation may be necessary to better determine the source of the effects of IL-10, and its relevance to human airway inflammatory diseases.…”

“…In fact, the reported effects of IL-10 on AHR have been variable, being decreased, unchanged, or increased, and may be dependent on the model employed. However, paradoxically decreased AHR with a lack of IL-10 has been reported in several mouse models of airway inflammation, as has re-establishment of AHR with administration of IL-10 [58][59][60][61][62][63][64][65]. Furthermore, Wilson et al [66] reported that the reduced pathological responses in IL-10 knockout mice were associated with increased production of IL-13R 2.…”

Intranasal CpG Therapy Attenuated Experimental Fungal Asthma in a TLR9-Dependent and -Independent Manner

“…Changes in IL-10 following IN CpG were also TLR9 dependent. The inhibitory effects of IL-10 on allergic inflammation are well known and include regulation of eosinophilia [8], inhibition of the proliferation of various structural cell types [41], and regulation of airway inflammation through its inhibitory action on nitric oxide, a potent mediator of AHR [42,43]. Recent studies have shown that the adoptive transfer of IL-10-overexpressing DCs into OVA-sensitized and challenged mice ameliorates allergic asthma symptoms [44].…”