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Cytokine-Mediated Crosstalk between Immune Cells and Epithelial Cells in the Gut.

ABSTRACT: Cytokines are small proteins that are secreted by a vast majority of cell types in the gut. They not only establish cell-to-cell interactions and facilitate cellular signaling, but also regulate both innate and adaptive immune responses, thereby playing a central role in genetic, inflammatory, and infectious diseases of the gut. Both, immune cells and gut epithelial cells, play important roles in intestinal disease development. The epithelium is located in between the mucosal immune system and the gut microbiome. It not only establishes an efficient barrier against gut microbes, but it also signals information from the gut lumen and its composition to the immune cell compartment. Communication across the epithelial cell layer also occurs in the other direction. Intestinal epithelial cells respond to immune cell cytokines and their response influences and shapes the microbial community within the gut lumen. Thus, the epithelium should be seen as a translator or a moderator between the microbiota and the mucosal immune system. Proper communication across the epithelium seems to be a key to gut homeostasis. Indeed, current genome-wide association studies for intestinal disorders have identified several disease susceptibility loci, which map cytokine signatures and their related signaling genes. A thorough understanding of this tightly regulated cytokine signaling network is crucial. The main objective of this review was to shed light on how cytokines can orchestrate epithelial functions such as proliferation, cell death, permeability, microbe interaction, and barrier maintenance, thereby safeguarding host health. In addition, cytokine-mediated therapy for inflammation and cancer are discussed.

SUBMITTER: Mahapatro M

PROVIDER: S-EPMC7827439 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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Cytokine-Mediated Crosstalk between Immune Cells and Epithelial Cells in the Gut.

Mahapatro Mousumi M Erkert Lena L Becker Christoph C

Cells 20210109 1

Cytokines are small proteins that are secreted by a vast majority of cell types in the gut. They not only establish cell-to-cell interactions and facilitate cellular signaling, but also regulate both innate and adaptive immune responses, thereby playing a central role in genetic, inflammatory, and infectious diseases of the gut. Both, immune cells and gut epithelial cells, play important roles in intestinal disease development. The epithelium is located in between the mucosal immune system and t ...[more]

PMID: 33435303

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Project description:Background & aimsCytokine-induced killer (CIK) cell-based immunotherapy is effective as an adjuvant therapy in early stage hepatocellular carcinoma (HCC) but lacks efficacy in advanced HCC. We aimed to investigate immune suppressor mechanisms in HCC, focusing on the role of myeloid-derived suppressor cells (MDSCs) in response to CIK therapy.MethodsMDSCs were quantified by flow cytometry and quantitative real-time PCR. Cytokines were detected by cytokine array. A lactate dehydrogenase cytotoxicity assay was performed in the presence or absence of MDSCs to study CIK function against HCC cells in vitro. An FDA-approved PDE5 inhibitor, tadalafil, was used to target MDSCs in vitro and in vivo. Two different murine HCC cell lines were tested in subcutaneous and orthotopic tumor models in C57BL/6 and BALB/c mice. The antitumor effects of human CIKs and MDSCs were also tested in vitro.ResultsAdoptive cell transfer of CIKs into tumor-bearing mice induced inflammatory mediators (e.g., CX3CL1, IL-13) in the tumor microenvironment and an increase of tumor-infiltrating MDSCs, leading to impaired antitumor activity in 2 different HCC models. MDSCs efficiently suppressed the cytotoxic activity of CIKs in vitro. In contrast, treatment with a PDE5 inhibitor reversed the MDSC suppressor function via ARG1 and iNOS blockade and systemic treatment with a PDE5 inhibitor prevented MDSC accumulation in the tumor microenvironment upon CIK cell therapy and increased its antitumor efficacy. Similar results were observed when human CIKs were tested in vitro in the presence of CD14+HLA-DR-/low MDSCs. Treatment of MDSCs with a PDE5 inhibitor suppressed MDSC suppressor function and enhanced CIK activity against human HCC cell lines in vitro.ConclusionOur results suggest that targeting MDSCs is an efficient strategy to enhance the antitumor efficacy of CIKs for the treatment of patients with HCC.Lay summaryCytokine-induced killer cells are a mixture of immune cells given to eliminate cancer cells. However, not all patients respond to this treatment. Herein, we show in 2 different liver cancer models that myeloid-derived suppressor cells are increased in response to cytokine-induced killer cell therapy. Targeting these myeloid-derived suppressor cells may provide an additional therapeutic benefit alongside cytokine-induced killer cell therapy.

Dataset Information

Cytokine-Mediated Crosstalk between Immune Cells and Epithelial Cells in the Gut.

Publications

Cytokine-Mediated Crosstalk between Immune Cells and Epithelial Cells in the Gut.

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