Research Article - Biomedical Research (2022) Volume 33, Issue 1

Kruppel-like factor-4 in macrophages synergistically regulates polarization with glucocorticoids and may ameliorate glucocorticoid resistance.

Kruppel-Like Factor-4 (KLF4) and Glucocorticoids (GCs), as fundamental therapies in Interstitial Lung Disease (ILD), can both promote macrophage polarization towards the M₂ subset, while there has been little evidence regarding whether KLF4 and GCs synergistically regulate polarization to induce lung tissue repair and enhance the activity of the Glucocorticoid Receptor (GR) pathway to ameliorate GC resistance. Macrophages were stimulated with Lipopolysaccharide (LPS) to induce an ILD model and divided into three cell lines: mKLF4 (KLF4 overexpression), shKLF4 (KLF4 knockdown) and negative control. Quantitative real-time PCR (qRT-PCR), ELISA and western blotting were used to evaluate the marker mRNA and protein expression of M₁/M₂ subsets as well as the marker protein expression of the GR pathway. M₂ marker mRNA and protein levels were elevated in mKLF4 cells but reduced in shKLF4 cells when stimulated with Dexamethasone (DX). In addition, decreased M₁ marker mRNA and protein levels in mKLF4 cells were observed in the study. Interestingly, M₁ marker mRNA and protein levels in shKLF4 cells were both reduced. Regarding the effect of KLF4 on GR pathways, the upregulated and downregulated levels of the marker protein GR and Histone Deacetylase 2 (HDAC2) in mKLF4 and shKLF4 cells support that KLF4 and GCs cooperate to enhance the expression of GR pathway proteins. KLF4 and GCs act in concert to promote macrophage polarization towards the M₂ subset and enhance the activity of the GR pathway to ameliorate GC resistance. Author(s): Hanyu Shi, Dawei Yin, Luqing Wei, Liang Sun

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