The promoter region of harbours p53-, IRF-1- and STAT1-binding sites, and accordingly BCL-G induction was observed during p53-mediated apoptosis9 and following stimulation with type I and type II interferons10. their mRNA levels decreased in active inflammatory bowel diseases (for BCL-GS) and colorectal malignancy (for BCL-GS/L). In vitro studies revealed that IFN- and TNF- synergised to upregulate BCL-GS/L and to trigger apoptosis in colonic epithelial cell lines and main human colonic organoids. Using RNAi, we showed that synergistic induction of IEC death was STAT1-dependent while optimal expression of BCL-GS/L required STAT1, NF-B/p65 and SWI/SNF-associated chromatin remodellers BRM and BRG1. To test the direct contribution of BCL-G to the effects of IFN- and TNF- on epithelial cells, we used RNAi- and CRISPR/Cas9-based perturbations in parallel with isoform-specific overexpression of BCL-G, and found that BCL-G was dispensable for Th1 cytokine-induced apoptosis of human IEC. Instead, Oleandrin we discovered that depletion of BCL-G differentially affected secretion of inflammatory chemokines CCL5 and CCL20, thus uncovering a non-apoptotic immunoregulatory function of this BCL-2 family member. Taken together, our data show that BCL-G may be involved in shaping immune responses in the human gut in health and disease says through regulation of chemokine secretion rather than intestinal apoptosis. gene is located in chromosome 12p12 tumour suppressor locus7, and through alternate splicing produces two unique isoforms: BCL-GS (short) and BCL-GL (long). The short isoform contains only a BH3 domain name and when overexpressed is usually a potent inducer of apoptosis, acting reportedly through sequestration of the pro-survival function of BCL-XL4. Conversely, BCL-GL possesses both BH2 and BH3 domains, has a limited killing capacity4 and thus closely resembles another weakly apoptogenic family member, Bfk8. Initial profiling of adult human tissues revealed that expression of BCL-GS was restricted to male reproductive organs, while BCL-GL was detected Oleandrin in various anatomical locations4. Little is known, however, about the physiological regulation of BCL-G expression and its functional effects. The promoter region of harbours p53-, IRF-1- and STAT1-binding sites, and accordingly BCL-G induction was observed during p53-mediated apoptosis9 and following activation with type I and type II interferons10. Of notice, loss of BCL-G attenuated UV-induced apoptosis of breast11 and prostate12 malignancy cells as well as conferred resistance to hypoxia and cisplatin-induced toxicity in kidney epithelial cells13, supporting its proposed role in cell death signalling. However, recent phenotypic analyses of Bcl-G-deficient mice challenged this notion and provided important insight into possible physiological functions of this orphan BCL-2 family member5,6,14. In mice, the gene encodes a single transcript homologous to human BCL-GL and while its tissue distribution pattern closely resembled that Oleandrin of BCL-GL, Bcl-g was also highly expressed across the murine gut5 including LGR5+ colonic stem cells6. Bcl-G knockout mice developed normally with intact gastrointestinal homoeostasis and offered no indicators of spontaneous (colonic) hyperplasia5,6, a functional manifestation often linked to a loss of a pro-apoptotic effector15. In particular, splenic dendritic cells lacking Bcl-G remained sensitive to spontaneous ex lover vivo apoptosis5, while data from colitis-associated or genetic models of colorectal malignancy showed unperturbed capsase-3 activation in Bcl-G?/? tumours6. Taken together, these elegant studies exhibited that mouse Bcl-G is not a pro-apoptotic regulator. Multiple signalling pathways control the balance between cellular proliferation, differentiation and cell death, and therefore are critical for maintaining tissue (and ultimately organismal) homoeostasis16. However, disruption of this dynamic equilibrium by an abnormal increase in cell death is usually a pathophysiological hallmark of numerous chronic disease says, including inflammatory bowel diseases (IBD) ulcerative colitis (UC) and Crohns disease (CD) which are remitting and relapsing multi-factorial inflammatory diseases of the gut16,17. An aberrantly high rate of intestinal epithelial cell (IEC) apoptosis in IBD prospects to Oleandrin a positive opinions loop of epithelial barrier disruption, microbiota-driven activation of inflammatory responses and further progressive tissue damage, in addition to pathological immune activation through the release of alarmins from dying IEC18. This epithelial damage response is usually often initiated and driven by cytokines associated with Th1 type immunity, in particular by IFN- and TNF-, IKK-beta which are known to induce death of IEC17. In this study, we analysed the expression of BCL-G in human gastrointestinal tissues in health and disease says, and decided its contribution to Th1 cytokine-induced colonic epithelial tissue damage. We statement that IFN- and TNF- synergised to induce BCL-G expression and apoptosis in both colonic epithelial cell lines and main human colonic organoids. Although upregulated during this damage response, human BCL-G much like its mouse homologue was dispensable for cell death. Instead, we discovered a non-apoptotic, immunomodulatory role of BCL-G in regulation of chemokine secretion. When combined with the observed high colonic expression of human BCL-G.