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IL-3 coordination of myeloblast function by modulating mRNA stability

ABSTRACT: The growth factor interleukin-3 (IL-3) promotes the survival and growth of multipotent hematopoietic progenitors and stimulates myelopoiesis. It has also been reported to oppose terminal granulopoiesis and to support leukemic cell growth through autocrine or paracrine mechanisms. We used kinetic microarray, Northern Blotting and bioinformatics analysis of IL-3 dependent myeloblasts to determine whether IL-3 acts in part by regulating the rate of turnover of mRNA transcripts in specific functional pathways. Our results indicate that exposure of myeloblasts to IL-3 causes immediate early stabilization of hundreds of transcripts in pathways relevant to myeloblast function. Examples include transcripts associated with proliferation and leukemic transformation (pik3cd, myb, pim-1), hematopoietic development (cited2), differentiation control (cdkn1a) and RNA processing (BRF1, BRF2). A domain in the 3’-utr of IL-6 that mediates IL-3 responsiveness contains AU-rich elements that bind proteins known to modulate mRNA stability, however a known destabilizing protein (AUF1) is shown not to mediate degradation in the absence of IL-3. These findings support a model of IL-3 action through mRNA stability control and suggest that aberrant stabilization of this network of transcripts could contribute to growth patterns observed in leukemia.

ORGANISM(S): Mus musculus

PROVIDER: GSE12067 | GEO | 2009/06/01

SECONDARY ACCESSION(S): PRJNA113315

REPOSITORIES: GEO

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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.

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IL-3 coordination of myeloblast function by modulating mRNA stability

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