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  • Upon LPS stimulation ERK and


    Upon LPS stimulation, ERK and STAT3 signaling pathways were activated in a time-dependent manner, and the phosphorylation of Y705 occurred later than that of S727 (Supplementary Fig. S5B). STAT3 is known to be phosphorylated on serine 727 (S727) by the mitogen-activated protein (MAP) kinase pathway to obtain maximal activation (Wen et al., 1995). Correspondingly, the phosphorylation of STAT3 on S727 was found to be suppressed by the MEK/ERK inhibitor while the STAT3 inhibitor had no effect on the MEK/ERK signaling pathway (Fig. 5B), implying that LPS stimulation might trigger the ERK activation to phosphorylate STAT3 on S727. Previous study has reported that Hif1a transcription was regulated by p-STAT3727 via binding to Hif1a promoter (Meng et al., 2018), and we casin found that HIF-1α expression was suppressed by ERK and STAT3 inhibitors (Fig. 5C), implying that HIF-1α expression was regulated by STAT3 signaling pathway. IL10 has been reported to be indispensable for CD11b expression. Upon LPS stimulation in vitro, CD11b expression was much lower in IL-10-/- casin than that in IL-10+/+B cells (Liu et al., 2015). We also analyzed CD11b expression in IL10+ or IL-10- B cells during the colitis process in vivo, and found that most of the IL10+B cells expressed CD11b while only a small fraction of IL-10- B cells expressed CD11b (Supplementary Fig. S5D), suggesting that CD11b expression was regulated by IL-10. Furthermore, IL-10 production and secretion were suppressed under the treatment of HIF-1α inhibitor LW6 (Supplementary Fig. S3). Therefore, IL-10 was suggested to be involved in HIF-1α-regulated CD11b expression, which was verified by the treatment of ERK, STAT3 (Fig. 5D, E), implying that IL-10-regulated CD11b expression was HIF-1α- dependent. STAT3 has been identified to be activated by secreted IL-10 cytokine through phosphorylation on Y705 (Ouyang et al., 2011) and then homodimerizes and translocates to the nucleus to promote target gene transcription (Wen et al., 1995). Consistent with these findings, we found that recombinant mouse IL-10 promoted the phosphorylation of STAT3 on Y705 (Supplementary Fig. S5C). Finally, the ChIP assay suggested that p-STAT3 translocated to the nucleus and formed a complex with HIF-1α to bind onto the HRE regions to facilitate the transcriptional regulation of CD11b (Fig. 5F). In summary, we revealed that HIF-1α may participate in lymphocyte-mediated inflammation or immune response via regulating the transcription of CD11b in B cells. Notably, HIF-1α appears to form a transcriptional complex with p-STAT3 and then binds onto HRE II or HRE IV regions in the Itgam promoter. This study provides more evidence for CD11b as a marker for regulatory B cells and provides a fresh therapeutic approach and insight regarding the treatment of colitis.
    Materials and Methods
    Introduction Gliomas are the most common primary malignant brain tumors. Despite a deeper molecular understanding of the disease, survival rates have not changed dramatically in the past several decades, and high-grade glioma remains one of the most lethal cancers. Both genotypic and phenotypic intratumoral heterogeneity have been proposed as key factors underlying the lack of long-term therapeutic response to aggressive treatment. Specifically, tumor cells with stem cell characteristics have been suggested to underlie therapeutic resistance and tumor recurrence in high-grade glioma. Intriguingly, the maintenance of stem cell phenotypes appears to be regulated by the tumor microenvironment in addition to specific genetic aberrations. Glioma cells with stem cell characteristics appear to be restricted primarily to specific tumor niches, most frequently in perinecrotic (hypoxic) and/or perivascular tumor areas. It is likely that these localizations are not random: microenvironmental cues unique to the perivascular microenvironment have been demonstrated to enhance glioma stem cell characteristics [1], [2], and hypoxia-inducible factors (HIF-1α and HIF-2α) elevated in perinecrotic tumor areas are central transcriptional regulators of the stem cell phenotype [3], [4].