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Comprehensive analysis of gene expression induced by IFN-γ in the human oral mucosal epithelial cell line HSC-2

ABSTRACT: Lipopolysaccharide (LPS) derived from Gram-negative bacteria is recognized by Toll-like receptor 4 (TLR4) on the host cell surface and by inflammatory caspases such as caspase-4 (CASP4) in the cytoplasm. LPS from the periodontal pathogen Porphyromonas gingivalis (PgLPS) is known to be recognized by TLR4, but whether it is sensed in the cytoplasm remains unclear. We investigated the intracellular recognition mechanism of PgLPS using the oral epithelial cell line HSC-2. Transfection of PgLPS alone did not elicit a response in HSC-2 cells; however, when PgLPS was transfected following priming with interferon (IFN)-γ, maturation of IL-18, activation of gasdermin D, and pyroptotic cell death were induced. These responses of HSC-2 cells were unaffected by TLR4 inhibition but were strongly suppressed by CASP4 inhibition. These findings suggest that IFN-γ–inducible genes likely play an auxiliary role in the CASP4-dependent responses of HSC-2 cells induced by PgLPS transfection. To examine the impact of IFN-γ priming on HSC-2 cells, we performed RNA sequencing (RNA-seq). This analysis identified 974 genes whose expression was upregulated by IFN-γ. Among these genes were members of the guanylate-binding protein (GBP) family (GBP1–5, GBP7) as well as CASP5. This analysis provides useful insights into the effects of IFN-γ on oral epithelial cells and into the characterization of IFN-stimulated factors in HSC-2 cells.

ORGANISM(S): Homo sapiens

PROVIDER: GSE306855 | GEO | 2025/08/31

REPOSITORIES: GEO

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Project description:Interferon (IFN)γ and interleukin (IL)-4 are central regulators of T helper 1 (Th1) and T helper 2 (Th2) immune responses, respectively. Both cytokines have a major impact on macrophage phenotypes: IFNγ–priming and subsequent TLR4 activation induces so called classically activated macrophages that are characterized by pronounced pro-inflammatory responses, whereas IL-4–treated macrophages, commonly called alternatively activated, are known to develop enhanced capacity for endocytosis, antigen presentation, and tissue repair and are generally considered anti-inflammatory. Considering IL-4 as priming rather than activating stimulus, we now compared the TLR4–dependent global gene activation program in IFNγ– versus IL-4–pretreated mouse macrophages, which has rarely been studied so far. Although both cytokines frequently induced opposing effects on gene transcription, the subsequent activation of bone marrow-derived macrophages by lipopolysaccharide (LPS) produced a strong, priming dependent pro-inflammatory response in both macrophage types. For example, the production of key pro-inflammatory cytokines IL-6 and IL-12 was significantly higher in IL-4– versus IFNγ–primed macrophages and several cytokine genes, including Il19, Ccl17, Ccl22, Ccl24 and Cxcl5, were preferentially induced in alternatively primed and LPS activated mouse macrophages. In a subset of genes, including IL12a, IFNγ priming was actually found to suppress LPS–induced gene expression in a Stat1–dependent manner. Our data suggest that IL-4–priming is not per se anti-inflammatory but generates a macrophage that is “tissue protective” but still capable of mounting a strong inflammatory response after TLR4–dependent activation. Keywords: Gene expression profiling Gene expression was investigated in mouse bone marrow-derived macrophages (BMM). On day 7, BMM were stimulated with either IL-4 or IFNγ overnight (18h in total). LPS treatment was performed in primed and unprimed macrophages 4 h prior to harvesting. At least three independent experiments were performed for each condition.

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Comprehensive analysis of gene expression induced by IFN-γ in the human oral mucosal epithelial cell line HSC-2

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