Journal of Interferon & Cytokine Research

Interleukin (IL)-15 belongs to the common gamma-dependent cytokine family, along with IL-2, IL-4, IL-7, IL-9, and IL-21. IL-15 is crucial for the homeostasis of Natural Killer (NK) and memory CD8 T cells, and to fight against cancer progression. However, dysregulations of IL-15 expression could occur and participate in the emergence of autoimmune inflammatory diseases as well as hematological malignancies. It is therefore important to understand the different modes of action of IL-15 to decrease its harmful action in pathology without affecting its beneficial effects in the immune system. In this review, we present the different approaches used by researchers to inhibit the action of IL-15, from most broad to the most selective. Indeed, it appears that it is important to selectively target the mode of action of the cytokine rather than the cytokine itself as they are involved in numerous biological processes.

Hypertrophic scar (HS) is a severe skin fibrotic disorder with unclear pathogenesis. Interferon-α2b (IFN-α2b) exerts inhibitory effects on HS in vivo and in vitro; however, the exact mechanism remains unclear. In this study, we aimed to evaluate the inhibitory effects of IFN-α2b on hypertrophic scar fibroblasts' (HSFs) proliferation and migration, and to further investigate the associated molecular mechanism. Cell Counting Kit-8 and CyQUANT assays were used to assess HSFs' proliferation; wound healing and Transwell assays were used to assess HSFs' migration; real-time quantitative polymerase chain reaction and Western blotting were used to detect messenger RNA and protein levels, respectively, of related genes; bioinformatics analysis was performed to predict the downstream target of IFN-α2b. Our findings are as follows: (1) IFN-α2b inhibited HSFs' proliferation and migration in a dose-dependent manner. (2) IFN-α2b inhibited HSFs' proliferation and migration by suppressing the Wnt/β-catenin pathway. (3) Retinoic-acid receptor responder 3 (RARRES3) was predicted as a functional downstream molecule of IFN-α2b, which was low in HSFs. (4) IFN-α2b inhibited HSF phenotypes and the Wnt/β-catenin pathway by upregulating RARRES3 expression. (5) RARRES3 restrained HSFs' proliferation and migration by repressing the Wnt/β-catenin pathway. In conclusion, IFN-α2b-induced RARRES3 upregulation inhibited HSFs' proliferation and migration through Wnt/β-catenin pathway suppression.

The human beta-coronavirus strain, OC43, provides a useful model for testing the antiviral activity of various agents. We compared the activity of several antiviral drugs against OC43, including remdesivir, chloroquine, interferon (IFN)-β, IFN-λ1, and IFN-λ4, in two distinct cell types: human colorectal carcinoma cell line (HCT-8 cells) and normal human bronchial epithelial (NHBE) cells. We also tested whether these agents mediate additive, synergistic, or antagonistic activity against OC43 infection when used in combination. When used as single agents, remdesivir exhibited stronger antiviral activity than chloroquine, and IFN-β exhibited stronger activity than IFN-λ1 or IFN-λ4 against OC43 in both HCT-8 and NHBE cells. Anakinra (IL-1 inhibitor) and tocilizumab (IL-6 inhibitor) did not mediate any antiviral activity. The combination of IFN-β plus chloroquine or remdesivir resulted in higher synergy scores and higher expression of IFN-stimulated genes than did IFN-β alone. In contrast, the combination of remdesivir plus chloroquine resulted in an antagonistic interaction in NHBE cells. Our findings indicate that the combined use of IFN-β plus remdesivir or chloroquine induces maximal antiviral activity against human coronavirus strain OC43 in primary human respiratory epithelial cells. Furthermore, our experimental OC43 virus infection model provides an excellent method for evaluating the biological activity of antiviral drugs.

High altitude hypoxia can lead to a spectrum of gastrointestinal problems. As the first line of host immune defense, innate immune response in the intestinal mucosa plays a pivotal role in maintaining intestinal homeostasis and protecting against intestinal injury at high altitude. This study aimed to investigate the effect of hypoxia on the colonic mucosal barrier and toll-like receptor 4 (TLR4)-mediated innate immune responses in the colon. The mice were exposed to a hypobaric chamber to simulate a 5,000 m plateau environment for 7 days, and the colonic mucosa changes were recorded. At the same time, the inflammation model was established by lipopolysaccharide (LPS) to explore the effects of hypoxia on the TLR4/nuclear factor kappa B (NF-κB) signaling pathway and its downstream inflammatory factors [tumor necrosis factor-α, interleukin (IL)-1β, IL-6, and interferon (IFN)-γ] in the colon. We found that hypoxic exposure caused weight loss and structural disturbance of the colonic mucosa in mice. Compared with the control group, the protein levels of TLR4 [fold change (FC) = 0.75 versus FC = 0.23], MyD88 (FC = 0.80 versus FC = 0.30), TIR-domain-containing adaptor protein inducing interferon-β (TRIF: FC = 0.89 versus FC = 0.38), and NF-κB p65 (FC = 0.75 versus FC = 0.24) in the colon of mice in the hypobaric hypoxia group were significantly decreased. LPS-induced upregulation of the TLR4/NF-κB signaling and its downstream inflammatory factors was inhibited by hypoxia. Specifically, compared with the LPS group, the protein levels of TLR4 (FC = 1.18, FC = 0.86), MyD88 (FC = 1.20, FC = 0.80), TRIF (FC = 1.20, FC = 0.86), and NF-κB p65 (FC = 1.29, FC = 0.62) and the mRNA levels of IL-1β (FC = 7.38, FC = 5.06), IL-6 (FC = 16.06, FC = 9.22), and IFN-γ (FC = 2.01, FC = 1.16) were reduced in the hypobaric hypoxia plus LPS group. Our findings imply that hypoxia could lead to marked damage of the colonic mucosa and a reduction of TLR4-mediated colonic innate immune responses, potentially reducing host defense responses to colonic pathogens.