IL-6 amplifier activation in epithelial regions of bronchi after allogeneic lung transplantation

Abstract

The IL-6 amplifier, a positive feedback loop for NFκB signaling, which was originally found to be activated by IL-17A and IL-6 stimulation in non-immune cells, is molecularly a simultaneous activator of NFκB and signal transducer and activator of transcription 3 (STAT3), functionally a local chemokine inducer and pathologically a machinery for inflammation development. It has been shown that IL-6 amplifier activation in epithelial cells contributes to rejection responses in a mouse chronic rejection model that develops a bronchiolitis obliterans (BO)-like disease. We investigated whether the IL-6 amplifier is activated in BO regions of a human lung graft after allogeneic transplantation. NFκB and STAT3 molecules were phosphorylated in the epithelial regions of bronchi that localized in the BO regions. Additionally, chemokine ligand 2 (CCL2), and CD4(+) T cells and macrophages increased in these regions. Furthermore, human lung epithelial cells expressed CCL2 after stimulation by IFNγ in the presence of IL-6 and epidermal growth factor via enhanced STAT3 signaling, which parallels behavior seen in the mouse model. Thus, our results suggest that the IL-6 amplifier in the epithelial cells of grafts is involved in chronic rejection after lung transplantation, suggesting that the amplifier may be a valuable therapeutic target to prevent chronic rejection after lung transplantation.

Intermittent hypoxia‐induced epiregulin expression by IL‐6 production in human coronary artery smooth muscle cells

“…that the IL-6 amplifier, which acts as a chemokine inducer in nonimmune cells, simultaneously activated NFjB and signal transducer and activator of transcription 3 to induce cytokines, such as IL-6, and locally attracted various immune cells [44][45][46]. Recently, the involvement of EREG in the potentiation of the IL-6 amplifier was reported [19].…”

Inflammation Amplifier, a New Paradigm in Cancer Biology

“…1A; ref. 2). The inflammation amplifier, which is a chemokine inducer in type I collagen þ nonimmune cells, including endothelial cells, fibroblasts, glia cells, and epithelial cells, is activated by the simultaneous activation of NF-kB and STAT and locally infiltrates various immune cells (2)(3)(4)(5). In fact, the inflammation amplifier is activated by various soluble molecules, including IL-17, TNF-a, ErbB1 ligands, and norepinephrine, which act as NF-kB stimulators, and IL-6 and IFN-g, which act as STAT stimulators ( Fig.…”

Breakpoint Cluster Region–Mediated Inflammation Is Dependent on Casein Kinase II

“…The main functional molecules of the inflammation amplifier are chemokines and growth factors, which deregulate local homeostasis via an accumulation of various immune cells and proliferate various regional cells, whereas IL-6 mainly acts as fuel to maintain the activation of STAT3 (16,17). We have shown that the amplifier is activated in the affected tissues of several disease models and clinical samples (17)(18)(19) and that its blockade suppressed these models (17,19). Furthermore, we performed genome-wide screenings of the amplifier machinery, identified .1000 positive regulators, including BCR, and .500 targets of the inflammation amplifier, all of which carried significantly high numbers of inflammatory disease-associated genes (17).…”

“…We previously reported an inflammation-inducing mechanism, called the inflammation amplifier, in nonimmune cells such as synovial cells and endothelial cells (15), which is activated by a simultaneous stimulation of NF-kB and STAT3 and involved in the pathogenesis of several inflammatory disease models (17)(18)(19). By genome-wide screenings, we have identified that BCR is one of the positive regulators of the inflammation amplifier (17).…”