COX-1–derived thromboxane A2 plays an essential role in early B-cell development via regulation of JAK/STAT5 signaling in mouse

Abstract

• This study demonstrated an essential role of COX-1 in early B-cell development.• Low-dose aspirin may have a potential suppressive effect on B-cell development in humans.Cyclooxygenases (COXs) and their prostanoid products play important roles in a diverse range of physiological processes, including in the immune system. Here, we provide evidence that COX-1 is an essential regulator in early stages of B-cell development. COX-1-deficient mice displayed systematic reduction in total B cells, which was attributed to the arrest of early B-cell development from pro-B to pre-B stage. We further demonstrated that this defect was mediated through downregulation of the Janus kinase/signal transducer and activator of transcription 5 (JAK/STAT5) signaling and its target genes, including Pax5, in COX-1 2/2 mice. Mechanistic studies revealed that COX-1-derived thromboxane A 2 (TxA 2 ) could regulate JAK3/STAT5 signaling through the cyclic adenosine monophosphate-protein kinase A pathway, via binding with its receptor thromboxane A2 receptor (TP). Administration of the TP agonist could rescue the defective B-cell development and JAK/STAT5 signaling activity in COX-1-deficient mice. Moreover, administration of low-dose aspirin caused a significant reduction in total B cells in peripheral blood of healthy human volunteers, coincidentally with reduced TxA 2 production and downregulation of JAK/STAT5 signaling. Taken together, our results demonstrate that COX-1-derived TxA 2 plays a critical role in the stage transition of early B-cell development through regulation of JAK/STAT5 signaling and indicate a potential immune-suppressive effect of low-dose aspirin in humans. (Blood. 2014;124(10):1610-1621

Glucocorticoid Induces Hepatic Steatosis by Inhibiting Activating Transcription Factor 3 (ATF3)/S100A9 Protein Signaling in Granulocytic Myeloid-derived Suppressor Cells

“…Flow Cytometric Analysis and Sorting-Flow cytometric analysis and sorting were performed as described previously (40). Briefly, single-cell suspensions were prepared and stained with fluorochrome-conjugated antibodies.…”

“…qRT-PCR-Total RNA was extracted with TRIzol (Invitrogen) and was subjected to reverse transcription using reverse transcriptase (TAKARA) at 42°C for 15 min, and the resulting cDNA was amplified by PCR using gene-specific primers (40). The primers were designed based on genome-wide procedures using the Primer 3 program and cross-checked by a BLAST search of the NCBI database.…”

Regulation of inflammation by lipid mediators in oral diseases

“…Thromboxane A 2 plays an important role in thrombus formation through platelet activation and vascular reactivity (Ally and Horrobin, ; Fitzgerald, ; Daniel et al , ), and some compounds have antithrombotic effects by binding to TP receptors (Guerrero et al , ). As an immune modulator, TXA 2 regulates JAK3/STAT5 signaling to promote early B‐cell development (Yang et al , ) and mediates neutrophil control of the magnitude and spread of the immune response (Yang and Unanue, ). TXA 2 has been shown to promote cell proliferation in lung adenocarcinoma (Huang et al , ), implicating a potential role in cancer.…”

Transcriptional Regulation of the Human Thromboxane A2 Receptor Gene by Wilms’ Tumour (WT)

“…Furthermore, increased levels of TXA 2 and expression of its synthase and its T prostanoid receptor, the TP, occur in a number of prevalent cancers including, for example, strongly correlating with bladder (31), prostate (32,33), colorectal (34,35) and non-small-cell lung cancer (36). Mechanistically, the role of TXA 2 in neoplastic progression is at least partly explained by the ability of the TXA 2 -TP axis to regulate key mitogenic/ERK-and RhoA-mediated signalling cascades that contribute to tumour development and metastasis (12,14) and also by its ability to regulate local inflammation and immunity (37)(38)(39)(40)(41)(42), including within the tumour (Figure 2; summary of TXA 2 -TP signalling). Hence, aside from its regulation of ERK-and RhoA-mediated processes ( Figure 2) (12,14), TXA 2 is a potent proinflammatory and immune-modulatory agent being abundantly produced in monocytes/activated macrophages and promotes monocyte chemoattractant protein-1 expression in tumours, recruiting tumour-associated macrophages, and negatively regulates the interaction between T-cells and dendritic cells, a process essential for adaptive/acquired immunity (38,39,43,44).…”

“…Hence, aside from its regulation of ERK-and RhoA-mediated processes ( Figure 2) (12,14), TXA 2 is a potent proinflammatory and immune-modulatory agent being abundantly produced in monocytes/activated macrophages and promotes monocyte chemoattractant protein-1 expression in tumours, recruiting tumour-associated macrophages, and negatively regulates the interaction between T-cells and dendritic cells, a process essential for adaptive/acquired immunity (38,39,43,44). Moreover, TXA 2 is critical for early B-cell development, also with implications for its role in tumour-infiltrating B-cells (42,45). Hence, due to its role in tumour growth and metastasis combined with its ability to regulate local inflammation and immunity, the TXA 2 -TP axis can impact at multiple levels within the tumour environment.…”