IL-18 and IL-12 synergy induces matrix degrading enzymes in the lung

Abstract

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.

Interleukin-1 Superfamily and Cancer

“…Apparently, antiangiogenic effects in these findings may be caused due to IL-18-induced expression of other antiangiogenic cytokines, such as, for instance, IL-12. In accordance with previous findings, Cero et al (2012) observed that administration of recombinant murine IL-18 in mice caused significant elevation of pulmonary mRNA levels of MMP. Jiang et al (2003a) observed significant upregulation of IL-18 gene expression in highly metastatic cell line PLA801D.…”

Restriction of HIV-1 Replication in Primary Macrophages by IL-12 and IL-18 through the Upregulation of SAMHD1

“…IL-12/IL-18 also induce the release of a unique pattern of cytokines (IL-8, CCL22, CXCL-9, and CXCL10) that is different from the pattern given by other polarizing stimuli such as GM-CSF or IFN-g (1). IL-12 appears to cooperate or act synergistically with IL-18 in the control of intracellular parasite infection of macrophages (7) or bridging innate and adaptive immunity (8)(9)(10). Notably, treatment of differentiated macrophages with IL-12/ IL-18 but not with M-CSF induces the production of IFN-g (5,6,11).…”

Airway pressure release ventilation during ex vivo lung perfusion attenuates injury

“…While tissue level expression of IL-6 is correlated with increased neutrophil counts, EVLP may wash out the intermediary TNF-α signal. Additionally, IL-12 has been cited as a pro-inflammatory cytokine in the inflammosome pathway(24, 25). Our group has previously demonstrated benefit from IL-12 deregulation through the adenosine 2B pathway in a DCD lung EVLP model (Charles AATS 2016 Submitted JTCVS).…”