Non-redundant Functions of IL-6 Produced by Macrophages and Dendritic Cells in Allergic Airway Inflammation

Abstract

Asthma is a common inflammatory disease of the airway caused by a combination of genetic and environmental factors and characterized by airflow obstruction, wheezing, eosinophilia, and neutrophilia of lungs and sputum. Similar to other proinflammatory cytokines, IL-6 is elevated in asthma and plays an active role in this disease. However, the exact molecular mechanism of IL-6 involvement in the pathogenesis of asthma remains largely unknown and the major cellular source of pathogenic IL-6 has not been defined. In the present study, we used conditional gene targeting to demonstrate that macrophages and dendritic cells are the critical sources of pathogenic IL-6 in acute HDM-induced asthma in mice. Complete genetic inactivation of IL-6 ameliorated the disease with significant decrease in eosinophilia in the lungs. Specific ablation of IL-6 in macrophages reduced key indicators of type 2 allergic inflammation, including eosinophil and Th2 cell accumulation in the lungs, production of IgE and expression of asthma-associated inflammatory mediators. In contrast, mice with deficiency of IL-6 in dendritic cells demonstrated attenuated neutrophilic, but regular eosinophilic response in HDM-induced asthma. Taken together, our results indicate that IL-6 plays a pathogenic role in the HDM-induced asthma model and that lung macrophages and dendritic cells are the predominant sources of pathogenic IL-6 but contribute differently to the disease.

In vitro IL-6/IL-6R Trans-Signaling in Fibroblasts Releases Cytokines That May Be Linked to the Pathogenesis of IgG4-Related Disease

“…Indeed, IgG4-RD RI, rather than serum IgG4, is closely related to disease activity (23,38), indicating that the increased level of IL-6 was directly correlated with disease activity and was also involved in the development of IgG4-RD. As a critical pro-inflammatory factor, IL-6 is produced by both immune cells, as well as various types of tissue cells (e.g., fibroblasts, epithelial cells, and keratinocytes) under the stimulation of IL-1, TNF-α, PDGF, virus, doublestranded RNA, and c-AMP, and subsequently promotes the development of inflammatory and autoimmune diseases (54)(55)(56)(57)(58). However, whether tissue cells in the affected organs of IgG4-RD can produce IL-6 remains unclear.…”

“…As a critical pro-inflammatory factor, IL-6 is produced by both immune cells, as well as various types of tissue cells (e.g., fibroblasts, epithelial cells, and keratinocytes) under the stimulation of IL-1, TNF-α, PDGF, virus, double-stranded RNA, and c-AMP, and subsequently promotes the development of inflammatory and autoimmune diseases ( 54 – 58 ). However, whether tissue cells in the affected organs of IgG4-RD can produce IL-6 remains unclear.…”

Innate Immune Components That Regulate the Pathogenesis and Resolution of hRSV and hMPV Infections

“…IL-33 secretion was found to be induced by TLR7 agonists, suggesting a possible mechanism for IL-33 secretion during a hRSV infection [ 105 ]. Additionally, and even though a moderate amount of IL-6 promotes local inflammation and limits viral spreading, the uncontrolled secretion of IL-6 could result in harmful T H 2 polarization [ 155 ].…”

The anti-scarring effect of corneal stromal stem cell therapy is mediated by transforming growth factor β3

“…Since negligible TGFβ3 changes were detected when hCSSC alone was treated with IFNγ and LPS, the cytokine induction is suggested to be specifically associated to the presence of M1 macrophages, and possibly the secreted molecules from macrophages. The production of IL-1β and IL-6 from activated macrophages has been shown to upregulate TGFβ3 expression in chondrocytes [ 37 , 38 ]. Here, we show that CSSC might adopt a similar response to the activated macrophages.…”