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| Home > Publications database > Activation of integrin signaling up-regulates pro-inflammatory cytokines in JAK2-V617F positive hematopoietic cells. |
| Home > Publications database > Activation of integrin signaling up-regulates pro-inflammatory cytokines in JAK2-V617F positive hematopoietic cells. |
| Journal Article | DKFZ-2025-01666 |
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2025
Biomed Central
London
Abstract: The JAK2-V617F mutation is the most frequent driver mutation in a group of malignant hematopoietic disorders called myeloproliferative neoplasms (MPN). JAK2-V617F is a somatic mutation originating in a hematopoietic stem cell and results in constitutively activated JAK-STAT signaling. High levels of pro-inflammatory cytokines in the blood are a hallmark of MPN patients and are a key factor in the severe clinical symptoms seen in these patients. The molecular mechanisms underlying the up-regulation of inflammatory cytokines in JAK2-V617F mutated hematopoietic cells remain to be elucidated.32D myeloid progenitor cells expressing JAK2-wildtype (WT) and JAK2-V617F, respectively were employed. In addition, primary hematopoietic cells from the JAK2-V617F knock-in MPN mouse model were investigated. Integrin outside-in signaling upon binding of cells to the adhesion molecules VCAM-1/ICAM-1 was characterized by Western blotting of phosphorylated FAK, STAT3, p65, SYK and JNK. Regulation of mRNA and protein expression of IL-1α, IL-1β, IL-6, TNF and CXCL10 was measured by qPCR and ELISA. RNAseq and DNA methylation analysis in primary mouse JAK2-V617F granulocytes was performed. In JAK2-V617F knock-in mice, anti-integrin treatment was applied to evaluate the impact of activated integrin signaling on IL-1 blood levels in vivo.Integrin stimulation via the adhesion molecules VCAM-1/ICAM-1 activated integrin outside-in signaling including FAK, SYK, NFκB, and JNK. This induced strong mRNA expression of IL-1α, IL-1β, IL-6, TNF and CXCL10. In 32D cells, the presence of the JAK2-V617F mutation further increased VCAM-1/ICAM-1-induced mRNA and protein levels of IL-1α and IL-1β, and active caspase 1 expression. In primary granulocytes, integrin stimulation resulted in an activated mRNA signature of inflammatory cytokines. Consistent with the mRNA results, adhesion to VCAM-1/ICAM-1 induced an increase in intracellular IL-1α and IL-1β protein levels in 32D cells. However, in primary hematopoietic cells, up-regulation of inflammatory cytokines was not observed at the protein level in vitro, whereas, in vivo, blocking of integrin binding to VCAM-1/ICAM-1 was sufficient to reduce elevated IL-1α levels in the blood of JAK2-V617F mice.We conclude that integrin stimulation via the adhesion molecules VCAM-1/ICAM-1 activates integrin outside-in signaling, leading to the up-regulation of pro-inflammatory cytokines in both JAK2-mutated and non-mutated mouse hematopoietic cells.
Keyword(s): Janus Kinase 2: genetics (MeSH) ; Janus Kinase 2: metabolism (MeSH) ; Animals (MeSH) ; Cytokines: metabolism (MeSH) ; Cytokines: genetics (MeSH) ; Signal Transduction (MeSH) ; Up-Regulation (MeSH) ; Mice (MeSH) ; Hematopoietic Stem Cells: metabolism (MeSH) ; Integrins: metabolism (MeSH) ; Humans (MeSH) ; Mutation (MeSH) ; Myeloproliferative Disorders: genetics (MeSH) ; Adhesion ; ICAM-1 ; IL-1α ; IL-1β ; Inflammation ; Integrins ; JAK2-V617F ; MPN ; Pro-inflammatory cytokines ; VCAM-1 ; Janus Kinase 2 ; Cytokines ; Integrins ; Jak2 protein, mouse
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