Αρχειοθήκη ιστολογίου

Δευτέρα 22 Οκτωβρίου 2018

Inhaled IL-10 Suppresses Lung Tumorigenesis via Abrogation of Inflammatory Macrophage-Th17 Cell Axis [TUMOR IMMUNOLOGY]

Intratracheal administration of a novel IL-10 formulation suppressed IL-17–driven, CD4+ T cell–dependent tumorigenesis in the LSL-K-rasG12D murine lung cancer model. Analysis of lung lymphocyte populations demonstrated that antitumor activity of IL-10 was associated with a 5-fold decline in Th17 cell prevalence and a concurrent suppression of inflammatory M1-like macrophage activity. Further phenotypic characterization revealed that macrophages and dendritic cells, but not Th17 cells, expressed IL-10RA on the cell surface with the CD11b+F4/80+CX3CR1+ interstitial macrophages representing the dominant IL-10RA+ subset. Consistent with these observations, in vitro stimulation of sorted CD4+ T cells with IL-10 did not affect their ability to produce IL-17, whereas similar treatment of purified interstitial macrophages resulted in a dramatic M1 to M2 phenotypic switch. Importantly, preconditioning of macrophages (but not of CD4+ T cells) with IL-10 led to potent suppression of CD4+ T cell IL-17 production in an in vitro coculture assay, suggesting that IL-10 suppressed Th17 cell activity primarily via its upstream effects on macrophages. In support of this notion, in vivo macrophage depletion resulted in a 5-fold decline in Th17 cell numbers and a concurrent 6-fold reduction in tumor burden. Collectively, these data demonstrate that in the LSL-K-rasG12D murine lung cancer model, inflammatory macrophage–Th17 cell axis is critical to tumorigenesis and that IL-10 blocks this process primarily via a direct effect on the former. Inhaled IL-10 formulations may be of use in prophylaxis against lung cancer in high-risk patients.



https://ift.tt/2NYmkXY

Δεν υπάρχουν σχόλια:

Δημοσίευση σχολίου