Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P10721 (c-kit)
 6,575 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mouse bone marrow-derived mast cells (BMMC) developed with IL-3 generate prostaglandin D2 (PGD2) through the utilization of prostaglandin endoperoxide synthase (PGHS)-1 within several minutes of cross-linking the high affinity Fc receptor for IgE (Fc epsilon RI) by hapten-specific IgE and Ag. We now report that this immediate generation of PGD2 is followed by a 15-fold induction of steady-state transcripts for PGHS-2, with a maximum at 30 min, accompanied by transient expression of PGHS-2 protein. When BMMC were pretreated with c-kit ligand (KL) in combination with IL-10 for 2 h, sensitized with IgE, and activated with Ag, their expression of steady-state transcripts for PGHS-2 increased 111-fold and their expression of PGHS-2 protein was markedly enhanced, with maximal expression at 1 h and 5 h, respectively, after activation. These events were accompanied by PGD2 generation from 1 to 10 h after activation that accounted for approximately 50% of total PGD2 generation. The expression of PGHS-1 protein did not change during this period. The optimal priming interval for the effect of KL plus IL-10 on the IgE-dependent induction of PGHS-2 was 2 h, at which time only this particular cytokine combination acted synergistically with activation by IgE and Ag. In contrast, at 2 days the accessory cytokines that could provide priming with KL included IL-3 and IL-9 in addition to IL-10. Dexamethasone, which inhibited the expression of PGHS-2 but not PGHS-1, and NS-398, a selective inhibitor of PGHS-2, each suppressed the delayed phase but not the immediate phase of PGD2 generation. Conversely, valeryl salicylate, a selective inhibitor of PGHS-1, suppressed the immediate but not the delayed phase of PGD2 generation after cell priming and IgE-dependent activation.
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PMID:IgE-dependent activation of cytokine-primed mouse cultured mast cells induces a delayed phase of prostaglandin D2 generation via prostaglandin endoperoxide synthase-2. 759 6

The view that the two isoforms of prostaglandin-endoperoxide synthase (cyclooxygenase), PGHS-1 and PGHS-2, mediate physiologic and inflammatory processes, respectively, implies separate pathways of arachidonic acid metabolism with different benefits to the host. Functional segregation of these steps in endogenous arachidonic acid metabolism in a single cell in response to different stimuli is now demonstrated. When mouse bone marrow-derived mast cells developed in interleukin-3 (IL-3)-containing medium were cultured with c-kit ligand in combination with IL-10 and IL-1 beta, transient expression of PGHS-2 mRNA and protein occurred in a dose- and time-dependent fashion, accompanied by substantial release of prostaglandin D2 (PGD2) into the culture medium from 2 to 10 h. In contrast, induction of PGHS-2 did not mediate an increase in PGD2 generation in response to stimulation with IgE and antigen. After a longer period of culture, from 24 to 48 h, the expression of PGHS-1 increased, as did the increase in IgE/antigen-dependent generation of PGD2. Dexamethasone, which inhibited the induction of PGHS-2 but not PGHS-1, and a PGHS-2-selective inhibitor suppressed cytokine-induced PGD2 generation but not IgE-dependent PGD2 generation. Thus, at a time when both PGHS-1 and PGHS-2 are present in bone marrow-derived mast cells, they function independently by coupling to different stimulus-initiated pathways to PGD2 generation from endogenously derived arachidonic acid.
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PMID:Prostaglandin endoperoxide synthase-1 and -2 couple to different transmembrane stimuli to generate prostaglandin D2 in mouse bone marrow-derived mast cells. 807 53

The IL-7/IL-7R pathway is essential for lymphocyte development and disturbances in the pathway can lead to immune deficiency or T cell mediated destruction. Here, the effect of transient hyperexpression of IL-7 was investigated on immune regulation and allograft rejection under immunosuppression. An experimental in vivo immunosuppressive mouse model of IL-7 hyperexpression was developed using transgenic mice (C57BL/6 background) carrying a tetracycline inducible IL-7 expression cassette, which allowed the temporally controlled induction of IL-7 hyperexpression by Dexamethasone and Doxycycline treatment. Upon induction of IL-7, the B220+ c-kit+ Pro/Pre-B I compartment in the bone marrow increased as compared to control mice in a serum IL-7 concentration-correlated manner. IL-7 hyperexpression also preferentially increased the population size of memory CD8+ T cells in secondary lymphoid organs, and reduced the proportion of CD4+Foxp3+ T regulatory cells. Of relevance to disease, conventional CD4+ T cells from an IL-7-rich milieu escaped T regulatory cell-mediated suppression in vitro and in a model of autoimmune diabetes in vivo. These findings were validated using an IL-7/anti-IL7 complex treatment mouse model to create an IL-7 rich environment. To study the effect of IL-7 on islet graft survival in a mismatched allograft model, BALB/c mice were rendered diabetic by streptozotocin und transplanted with IL-7-inducible or control islets from C57BL/6 mice. As expected, Dexamethasone and Doxycycline treatment prolonged graft median survival as compared to the untreated control group in this transplantation mouse model. However, upon induction of local IL-7 hyperexpression in the transplanted islets, graft survival time was decreased and this was accompanied by an increased CD4+ and CD8+ T cell infiltration in the islets. Altogether, the findings show that transient elevations of IL-7 can impair immune regulation and lead to graft loss also under immune suppression.
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PMID:Inducible IL-7 Hyperexpression Influences Lymphocyte Homeostasis and Function and Increases Allograft Rejection. 3102 66