IL-18 and IL-12 induce inflammatory cytokines, chemokine ligand 9 (CXCL9) and T cell infiltration in pulmonary tissue

Background: Increased levels of interleukin (IL)-18 and IL-12 have been found during experimental alveolar hypoxia and in patients with COPD. Aims: To study the presence of IL-18 and IL-12 receptors (IL-18R/IL-12R) in the lungs and the effect of IL-18 and IL-12, alone or in combination, on the lungs with regard to inflammatory response and induction of emphysema related metalloproteinases (MMP2, MMP9, MMP12). Methods: Expression of IL-18R and IL-12R was studied in lungs, heart, liver and spleen in C57Bl/6 mice. 24 hours after a single i.p. dose of recombinant murine IL-18 alone, recombinant IL-12, IL-18+IL-12 or PBS (controls), lungs were harvested for immunohistochemical (IHC) and RT-PCR analyses. Results: The expression of IL-18R mRNA was 16-630-fold higher in lungs than in other organs. The expression of IL-12R was 4-fold higher in the spleen than in lungs. Mice treated with IL-18 or IL-12 alone showed significantly higher mRNA levels of interferon-γ, tumor necrosis factor-α and MMP12, than in controls (p<0,05). Mice treated with IL-18+IL-12 showed an even more pronounced induction of these mediators, as well as a significant increase in IL-6 and IL-1β(p<0,05). A marked increase in CXCL9 mRNA was induced by IL-18 (12-fold), IL-12 (19-fold), IL-18+IL-12 (153-fold). IHC showed perivascular T-cell infiltration following co-stimulation. Conclusions: High levels of IL-18 receptor suggest that the lungs might be a target organ for IL-18. IL-18+IL-12 exert a synergistic effect on the lungs by inducing inflammatory cytokines and MMP12 which may promote inflammation and emphysema. Induction of CXCL9 may be of importance for the observed T cell infiltration in lung tissue.