IL-18 and IL-12 synergy induces matrix degrading enzymes in the lung.
Interleukin (IL)-18 is a pro-inflammatory cytokine suggested to be involved in the development of pulmonary emphysema and inflammation. Studies involving immunology and cancer have revealed that IL-18 can have synergistic effects with IL-12. We have studied the presence of IL-18 and IL-12 receptors (IL-18R/IL-12R) in the lungs and whether IL-18 and IL-12, alone or in combination, have the ability to initiate the induction of mediators related to the development of emphysema and inflammation. The expression of the IL-18R was abundant in lungs compared to other organs (heart, liver, and spleen), and the IL-12R was also expressed in lung tissue. Mice treated with i.p. injection of recombinant murine IL-18 or IL-12 expressed significantly higher pulmonary mRNA levels of the matrix degrading enzymes metalloproteinase (MMP) 12 and cathepsin S, in addition to interferon-γ, tumor necrosis factor-α, and CXC chemokine ligand 9 (CXCL9) (all P < .05) than controls (received PBS). Treatment with IL-18 and IL-12 in combination showed an even more pronounced induction of these mediators, as well as a significant increase in MMP-9, IL-6, IL-1β, and transforming growth factor-β (P < .05). Furthermore, cellular apoptosis in lung tissue was induced. Immunohistochemical analysis revealed T-cell infiltration in pulmonary vessels following co-stimulation. In summary, IL-18 and IL-12 exert a synergistic effect on the lungs by inducing MMPs, cathepsins S, and pro-inflammatory cytokines, which may promote pulmonary emphysema and inflammation. The synergy between IL-18 and IL-12 involves infiltration of T-cells in the lungs, possibly induced by the T-cell chemoattractant CXCL9.
Department of Pulmonary Medicine, Oslo University Hospital Ullevål, University of Oslo, Oslo, Norway. cero.fadila@medisin.uio.no
Fadila Telarevic
FT
Cero
Vigdis
V
Hillestad
Else Marit
EM
Løberg
Geir
G
Christensen
Karl-Otto
KO
Larsen
Ole Henning
OH
Skjønsberg
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002403:Cathepsins / Q000096:biosynthesis* / Q000235:genetics; D004195:Disease Models, Animal; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D018664:Interleukin-12 / Q000494:pharmacology*; D020382:Interleukin-18 / Q000494:pharmacology*; D008168:Lung / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D053508:Matrix Metalloproteinase 12 / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000378:metabolism; D053707:Receptors, Interleukin-12 / Q000378:metabolism; D053724:Receptors, Interleukin-18 / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D013601:T-Lymphocytes / Q000378:metabolism / Q000473:pathology; D015854:Up-Regulation / Q000187:drug effects
D020382:Interleukin-18; D012333:RNA, Messenger; D053707:Receptors, Interleukin-12; D053724:Receptors, Interleukin-18; D011994:Recombinant Proteins; D018664:Interleukin-12; D002403:Cathepsins; C028217:cathepsin S; D053508:Matrix Metalloproteinase 12