Abstract
MKK3 is a member of the p38 MAPK signaling pathway and is an important factor in non allergic inflammatory and Th1 responses. Less is known about the role of MKK3 in allergic inflammation. We investigated the role of MKK3 in murine models of non-allergic and allergic lung inflammation. Wild Type (WT) mice were instillated with lipopolysaccharide (LPS) (10 μg, i.t) or zymosan (100μg i.t.). A significant increase in neutrophil numbers in the lung were observed 24h later compared to saline controls (saline: 0.3±0.01 vs LPS: 9.4±1.9; zymosan: 6.2±0.8×105/ml, n=9. p≤0.05) or MKK3-/- KO mice (LPS: 0.36±0.04; zymosan: 0.57±0.3×105/ml, n=10). WT mice also produced significant levels of IL-6, IL-12, TNF-α and INF-α as compared to saline mice. MKK3-/- mice did not release these cytokine in response to LPS or zymosan. WT mice were sensitized twice to ovalbumin (ova, 10mg/mouse i.p in alum). From day 14 all mice were exposed to 3% ova once daily for 3 days. Lung lavages were performed 24 h after the last exposure. Exposure to ova significantly increased eosinophils number in the lungs of ova-sensitized mice as compared with sham-immunized mice (sham: 0±0 vs ova WT: 0.45±0.11, n=11; ova MKK3-/-: 2.83±0.74, n=13×105/ml). Ova-MKK3-/- mice showed significant increase of IL-5 compared to WT ova and sham-immunized mice (sham: 0.38±0.98 vs ova WT: 3.5±1.9 and ova MKK3-/-: 20.8±10.7 pg/ml). MKK3-/- mice showed significantly higher levels of IgE compared to WT mice, irrespective of ova treatment (sham WT: 0±0; ova WT: 6062.3±560 pg/ml, n=6; sham MKK3-/-: 4414.5±637, ova MKK3-/-: 5328.8±415.8 pg/ml, n=13). In conclusion, MKK3 differentially regulates allergic and non-allergic responses in the lung.
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