LIGHT in Combination with IL-13 or IL-17 Drives Inflammatory Phenotypes in Human Pulmonary Fibroblasts
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1255484 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Fibroblasts are primary structural cells involved in tissue remodelling, but recent transcriptomic data have highlighted the ability of fibroblasts to display molecules that contribute to inflammation. Which factors might drive such inflammatory phenotypes are unclear. LIGHT (TNFSF14) is a cytokine that we previously showed was involved in inflammation of the lungs and may be central to lung diseases exhibiting fibrosis and inflammation, including asthma and interstitial lung disease. With RNA-seq, we investigated the activity of LIGHT in human pulmonary fibroblasts compared to IL-13 and IL-17, two other cytokines linked to lung disease. While all three cytokines individually induced both unique and overlapping gene transcripts, when fibroblasts were stimulated with LIGHT and IL-13 they upregulated more inflammatory transcripts including CCL2, CCL26, CXCL2, CXCL3, CXCL5, CXCL6, IL32, CSF2, VCAM1, ICAM1, IL18R1, IL1RL1, TNFRSF12A, TNFRSF4, TNFRSF8, ITGA2, ITGA4, and ITGAV; and when stimulated with LIGHT and IL-17, inflammatory transcripts included CXCL1, CXCL2, CXCL3, CXCL5, CXCL6, CXCL8, IL32, IL33, CSF2, TSLP, IL1A, IL6, IL18, VCAM1, ICAM1, IL18R1, IL1RL1, TNFSF4, TNFRSF4, TNFRSF8, ITGA2, ITGA4, and ITGAV. Furthermore, multiple cell cycle-related transcripts were induced with the combinations of LIGHT with IL-13 or IL-17. Providing physiological significance, some of the fibroblast transcriptional signatures induced by these cytokines were found to be present in subsets of fibroblasts isolated from patients with interstitial lung disease. This study highlights the synergistic activities of LIGHT in lung fibroblasts and suggests it could drive inflammatory activities relevant for several diseases dependent on the availability of other classical cytokines made in the lungs.
2025-07-10 | GSE295622 | GEO
Project description:Engineered cytokine-based approaches for immunotherapy of cancer are poised to enter the clinic, with IL-12 being at the forefront. However, little is known about potential mechanisms of resistance to cytokine therapies. We found that orthotopic murine lung tumors were resistant to systemically delivered IL-12 fused to murine serum albumin (MSA, IL12-MSA) due to low IL-12R expression on tumor-reactive CD8+ T cells. IL2-MSA increased binding of IL12-MSA by tumor-reactive CD8+ T cells, and combined administration of IL12-MSA and IL2-MSA led to enhanced tumor-reactive CD8+ T cell effector differentiation, decreased numbers of tumor-infiltrating CD4+ regulatory T (Treg) cells, and increased survival of lung tumor-bearing mice. Predictably, the combination of IL-2 and IL-12 at therapeutic doses led to significant dose-limiting toxicity. Administering IL-12 and IL-2 analogs with preferential binding to cells expressing IL12rb1 and CD25, respectively, led to a significant extension of survival in mice with lung tumors while abrogating dose-limiting toxicity. These findings suggest that IL-12 and IL-2 represent a rational approach to combination cytokine therapy whose dose-limiting toxicity can be overcome with engineered cytokine variants.
2024-01-26 | PXD044740 | Pride
Project description:IL-17 and TNF-alpha synergistically induce surface expression of IL-13Ra2 on primary lung fibroblasts, rendering them unresponsive to IL-13. Neutralizing antibodies to IL-13Ra2 restored IL-13-mediated signaling and transcriptome studies confirmed IL-13Ra2 is an IL-13 decoy receptor.
2014-12-31 | GSE56338 | GEO
Project description:Cytokines such as TNF-alpha and IL-1beta are known for their contribution to inflammatory processes in liver . In contrast, the cytokine IL-17 has not yet been assigned a role in liver diseases. IL-17 can cooperate with TNF-alpha to induce a synergistic response on several target genes in different cell lines, but no data exist for primary hepatocytes. To enhance our knowledge on the impact of IL-17 alone and combined with TNF-alpha in primary murine hepatocytes a comprehensive microarray study was designed. IL-1beta was included as this cytokine is suggested to act in a similar manner as the combination of TNF-alpha and IL-17, especially with respect to its role in mRNA stabilization. Results: The present microarray analysis demonstrates that primary murine hepatocytes responded to IL-17 stimulation by upregulation of chemokines and genes, which are functionally responsible to increase and sustain inflammation. Cxcl2, Nfkbiz and Zc3h12a were strongly induced, whereas the majority of the genes were only very moderately upregulated. Promoter analysis revealed involvement of NF-kappaB in the activation of many genes. Combined stimulation of TNF-alpha/IL-17 resulted in enhanced induction of gene expression, but significantly synergistic effects could be applied only to a few genes, such as Nfkbiz, Cxcl2, Zc3h12 and Steap4. Comparison of the gene expression profile obtained after stimulation of TNF-alpha/IL-17 versus IL-1 proposed a IL-1beta-like effect of the latter cytokine combination. Moreover, evidence was provided that modulation of mRNA stability may be a major mechanism by which IL-17 regulates gene expression in primary hepatocytes. This assumption was exemplarily proven for Nfkbiz mRNA for the first time in hepatocytes. Our studies also suggest that RNA stability can partially be correlated to the existence of AU rich elements, but further mechanisms like the RNase-activity of the upregulated Zc3h12a have to be considered. Conclusions: Our microarray analysis gives new insights in IL-17 induced gene expression in primary hepatocytes highlighting the crosstalk with the NF-kappaB signalling pathway. Gene expression profile suggests IL-17 a role in sustaining liver inflammatory processes most likely by RNA stabilization. Altogether, our results provide evidence that IL-17 alone and in concert with TNF-alpha may play a role in inflammatory liver diseases. Primary murine hepatocytes of three animals stimulated for 1 or 4h by TNF-alpha, IL-1beta, IL-17 or TNF-alpha followed by IL-17 were used for microarray analysis.
2010-03-07 | E-GEOD-19272 | biostudies-arrayexpress
Project description:The intestinal epithelium is our first line of defense against infections of the gut and the plasticity in cellular differentiation of the intestinal epithelium is an important part of this response. The changes in cellular composition is driven by immune cell derived cytokines. Here we use signature cytokines of different type of immune responses applied to small intestinal organoids to model how different immune responses affect intestinal epithelial development. Simplified, IL-13 represents type II immunity against infections such as parasites and IL-22 represents type III immunity against infections such as extracellular bacterial infections. 10 ng/mL of IL-13 and IL-22 was added for 72 hours after splitting. Furthermore, we have found BMP signaling to be important in regulating the cellular differentiation induced by IL-13. We therefore added added a combination treatment with the activin receptor-like kinase 2 (ALK-2) signaling inhibitor Dorsomorphin homolog 1 (DMH1) in concentration of 5 uM. We find that ALK-2 signaling is crucial for IL-13 driven Tuft cell differentiation.
2022-05-08 | E-MTAB-9185 | biostudies-arrayexpress
Project description:The IL-23/IL-17 immune axis is of central importance in psoriasis. However, the contribution of IL-17 family cytokines other than IL-17A to drive skin inflammation in psoriasis has not been fully established. To further elucidate the role of individual IL-17 family cytokines in psoriasis, we investigated their expression and localization in psoriasis skin at the mRNA and protein level. Moreover, we investigated the gene expression signatures induced by individual IL-17 family cytokines in human skin ex vivo as well as modulation of responses induced by the combination of IL-17 family cytokines in human keratinocytes by brodalumab, a human monoclonal antibody targeting the IL-17RA, versus the IL-17A blocking antibody ixekizumab. We demonstrate that IL-17A, IL-17AF, IL-17F and IL-17C are expressed at increased levels in psoriasis lesional skin and induce inflammatory gene expression signatures in human skin ex vivo that correlate with those observed in psoriasis. Furthermore, we show that brodalumab, in contrast to ixekizumab, fully blocks gene expression responses induced by the combination of IL-17A, IL-17AF, IL-17F and IL-17C in human keratinocytes. These findings suggest that inhibition of several IL-17 family cytokines, e.g. by targeting of the IL-17RA receptor, could be a favored mechanism to obtain a profound suppression of the inflammatory processes in psoriasis and thereby achieve high levels of skin clearance and sustained efficacy in patients with psoriasis.
2021-04-07 | GSE158448 | GEO
Project description:We used ChIP-seq to investigate epigenomic modifications in response to IFN-a, IL-17, and IL-13 in primary human bronchial epithelial cells (HBECs).
2022-05-24 | GSE185201 | GEO
Project description:Cytokines such as TNF-alpha and IL-1beta are known for their contribution to inflammatory processes in liver . In contrast, the cytokine IL-17 has not yet been assigned a role in liver diseases. IL-17 can cooperate with TNF-alpha to induce a synergistic response on several target genes in different cell lines, but no data exist for primary hepatocytes. To enhance our knowledge on the impact of IL-17 alone and combined with TNF-alpha in primary murine hepatocytes a comprehensive microarray study was designed. IL-1beta was included as this cytokine is suggested to act in a similar manner as the combination of TNF-alpha and IL-17, especially with respect to its role in mRNA stabilization. Results: The present microarray analysis demonstrates that primary murine hepatocytes responded to IL-17 stimulation by upregulation of chemokines and genes, which are functionally responsible to increase and sustain inflammation. Cxcl2, Nfkbiz and Zc3h12a were strongly induced, whereas the majority of the genes were only very moderately upregulated. Promoter analysis revealed involvement of NF-kappaB in the activation of many genes. Combined stimulation of TNF-alpha/IL-17 resulted in enhanced induction of gene expression, but significantly synergistic effects could be applied only to a few genes, such as Nfkbiz, Cxcl2, Zc3h12 and Steap4. Comparison of the gene expression profile obtained after stimulation of TNF-alpha/IL-17 versus IL-1 proposed a IL-1beta-like effect of the latter cytokine combination. Moreover, evidence was provided that modulation of mRNA stability may be a major mechanism by which IL-17 regulates gene expression in primary hepatocytes. This assumption was exemplarily proven for Nfkbiz mRNA for the first time in hepatocytes. Our studies also suggest that RNA stability can partially be correlated to the existence of AU rich elements, but further mechanisms like the RNase-activity of the upregulated Zc3h12a have to be considered. Conclusions: Our microarray analysis gives new insights in IL-17 induced gene expression in primary hepatocytes highlighting the crosstalk with the NF-kappaB signalling pathway. Gene expression profile suggests IL-17 a role in sustaining liver inflammatory processes most likely by RNA stabilization. Altogether, our results provide evidence that IL-17 alone and in concert with TNF-alpha may play a role in inflammatory liver diseases.
2010-03-01 | GSE19272 | GEO
Project description:We used bulk cell RNA-seq to investigate transcriptional effects of IFN-a, IL-17, and IL-13 in primary human bronchial epithelial cells (HBECs).
2022-05-24 | GSE185200 | GEO
Project description:Tumor-associated macrophages (TAM) represent an abundant cell population of the immune infiltrate in solid tumors and have been shown to orchestrate escape from immune surveillance. Macrophages display a very plastic phenotype which is recapitulated in vitro by classifying certain subsets according to exposure with defined, individual cytokines. The tumor-promoting M2 macrophages are polarized in vitro by differentiating human monocyte-derived macrophages with the T helper cell type 2 (Th2) response cytokines interleukin-4 and interleukin-13 or the immunosuppressive cytokine interleukin-10. Notably, only the latter macrophage subset undergoes apoptosis when treated with the colony stimulating factor 1 receptor (CSF1R) blocking antibody emactuzumab. However, under physiologic conditions the phenotype of TAM is shaped by a combination of cytokines. Hence, we evaluated if the addition of IL-10 to IL-4 or IL-13 differentiated macrophages is able to override IL-4/-13 mediated signaling and to restore susceptibility to emactuzumab. Though addition of IL-10 did not restore emactuzumab susceptibility, we surprisingly detected that only IL-4 differentiated macrophages sustained their specific marker expression while IL-10 skewed the IL-13 differentiated macrophage profile towards the IL-10 regulated phenotype. In-depth characterization by gene expression profiling revealed unique signatures of IL-4+IL-10 and IL-13+IL-10 differentiated macrophage subsets characterized by upregulation of the canonical NFκB signaling or Wnt/β-catenin signaling pathways, respectively. In silico-based analysis of a large cohort of cancer patients revealed distinct interleukin-4 or interleukin-13 overexpression patterns in a subset of patients with partial co-expression of IL-10 but almost absent IL-4/IL-13 co-expression. These patients may have less TAM depletion under therapy with CSF1R inhibitors. Five different macrophage subtypes were differentiated for six days with respect to different cytokines and transcriptomically profiled with three biological replicates derived from three different human, healthy volunteer donors
2016-08-06 | E-GEOD-85260 | biostudies-arrayexpress