6 research outputs found
Cyclic AMP suppresses interleukin-5 synthesis by human helper T cells via the downregulation of the calcium mobilization pathway
1. To delineate the mechanism by which cyclic AMP (cAMP) suppresses interleukin (IL)-5 synthesis, the effects of prostaglandin (PG) E(2), forskolin, dibutyryl (db)-cAMP and the Ca(2+) ionophore, ionomycin on cytokine synthesis, proliferation and CD25 expression of human T cells were investigated. Further studies were performed by measurement of the intracellular concentrations of cyclic AMP ([cAMP](i)) and Ca(2+) ([Ca(2+)](i)) and by electrophoretic mobility shift analysis (EMSA). 2. PGE(2), forskolin and db-cAMP suppressed IL-5 production by human T cell line following T cell receptor (TCR)-stimulation. PGE(2) suppressed TCR-induced messenger RNA (mRNA) expression of IL-2, IL-4 and IL-5, as well as proliferation and CD25 expression. 3. Cyclic AMP-mediated suppression of cytokine synthesis, proliferation and CD25 expression in human T cells were attenuated by ionomycin. 4. [cAMP](i) was increased by PGE(2) and forskolin. PGE(2) suppressed the TCR-induced biphasic increase in [Ca(2+)](i). EMSA revealed that four specific protein-DNA binding complexes related to NF-AT were detected at the IL-5 promoter sequence located from −119 to −90 relative to the transcription initiation site. The slowest migrating complex induced by TCR stimulation was enhanced by PGE(2) and further upregulated by ionomycin. Another binding which did not compete with cold AP-1 oligonucleotides, was constitutively present and was unaffected by PGE(2) but enhanced by ionomycin. 5. The suppressive effect of cyclic AMP on human IL-5 synthesis is mediated by interference with intracellular Ca(2+) mobilization but distinct from the NF-AT-related pathway
Potential role of phosphodiesterase 7 in human T cell function: comparative effects of two phosphodiesterase inhibitors
Even though the existence of phosphodiesterase (PDE) 7 in T cells has been proved, the lack of a selective PDE7 inhibitor has confounded an accurate assessment of PDE7 function in such cells. In order to elucidate the role of PDE7 in human T cell function, the effects of two PDE inhibitors on PDE7A activity, cytokine synthesis, proliferation and CD25 expression of human peripheral blood mononuclear cells (PBMC) were determined. Recombinant human PDE7A was obtained and subjected to cyclic AMP-hydrolysis assay. PBMC of Dermatophagoides farinae mite extract (Df)-sensitive donors were stimulated with the relevant antigen or an anti-CD3 monoclonal antibody (MoAb). PBMC produced IL-5 and proliferated in response to stimulation with Df, while stimulation with anti-CD3 MoAb induced CD25 expression and messenger RNA (mRNA) synthesis of IL-2, IL-4 and IL-5 in peripheral T cells. A PDE inhibitor, T-2585, which suppressed PDE4 isoenzyme with high potency (IC50 = 0·00013 μm) and PDE7A with low potency (IC50 = 1·7 μm) inhibited cytokine synthesis, proliferation and CD25 expression in the dose range at which the drug suppressed PDE7A activity. A potent selective inhibitor of PDE4 (IC50 = 0·00031 μm), RP 73401, which did not effectively suppress PDE7A (IC50 > 10 μm), inhibited the Df- and anti-CD3 MoAb-stimulated responses only weakly, even at 10 μm. PDE7 may play a critical role in the regulation of human T cell function, and thereby selective PDE7 inhibitors have the potential to be used to treat immunological and inflammatory disorders
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Age of Onset and Disease Course in Biopsy-Proven Minimal Change Disease: An Analysis From the Cure Glomerulopathy Network
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Association of COVID-19 Versus COVID-19 Vaccination With Kidney Function and Disease Activity in Primary Glomerular Disease: A Report of the Cure Glomerulonephropathy Study
Patients with glomerular disease (GN) may be at increased risk of severe COVID-19, yet concerns over vaccines causing disease relapse may lead to vaccine hesitancy. We examined the associations of COVID-19 with longitudinal kidney function and proteinuria and compared these to similar associations with COVID-19 vaccination.
Observational cohort study from July 1, 2021 to Jan. 1, 2023.
& Participants: A prospective observational study network of 71 centers from North America and Europe (CureGN) with children and adults with primary minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, or IgA nephropathy.
COVID-19 and COVID-19 vaccination.
Repeated measure of estimated glomerular filtration rate (eGFR); recurrent time-to-event outcome of GN disease worsening as defined by doubling of UPCR to at least 1.5g/g or increase in dipstick urine protein by two ordinal levels to 3+ (300mg/dL) or above.
Interrupted time series analysis for eGFR. Prognostic matched sequential stratification recurrent event analysis for GN disease worsening.
Among 2,055 participants, 722 (35%) reported COVID-19; of these, 92 (13%) were hospitalized and 3 died (<1%). eGFR slope pre-COVID-19 was -1.40ml/min/1.73m2 (SD 0.29), and -4.26ml/min/1.73m2 (SD 3.02) within 6 months post-COVID-19, which were not significantly different (p=0.34). COVID-19 was associated with increased risk of worsening GN disease activity (HR 1.35, 95% CI 1.01-1.80). Vaccination was not associated with change in eGFR (-1.34ml/min/1.73m2, SD 0.15 vs -2.16ml/min/1.73m2, SD 1.74; p=0.6) or subsequent GN disease worsening (HR 1.02, 95% CI 0.79–1.33) in this cohort.
Infrequent or short follow-up.
Among patients with primary GN, COVID-19 was severe for 1 in 8 cases and was associated with subsequent worsening of GN disease activity, as defined by proteinuria. In contrast, vaccination against COVID-19 was not associated with change in disease activity or kidney function decline. These results support COVID-19 vaccination for patients with GN.
In this cohort study of 2,055 patients with minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, or IgA nephropathy, COVID-19 resulted in hospitalization or death for 1 in 8 cases and was associated with a 35% increase in risk for worsening proteinuria. In contrast, vaccination did not appear to adversely affect kidney function or proteinuria. Our data support vaccination for COVID-19 in patients with glomerular disease