Anti-inflammatory effects of novel barbituric acid derivatives in T lymphocytes.
We have used a high throughput small molecule screen, using a fission yeast-based assay, to identify novel phosphodiesterase 7 (PDE7) inhibitors. One of the most effective hit compounds was BC12, a barbituric acid-based molecule that exhibits unusually potent immunosuppressive and immunomodulatory actions on T lymphocyte function, including inhibition of T cell proliferation and IL-2 cytokine production. BC12 treatment confers a >95% inhibition of IL-2 secretion in phytohaemagglutinin (PHA) plus phorbol-12-myristate-13-acetate (PMA) stimulated Jurkat T cells. The effect of BC12 on IL-2 secretion is not due to decreased cell viability; rather, BC12 blocks up-regulation of IL-2 transcription in activated T cells. BC12 also inhibits IL-2 secretion in human peripheral T lymphocytes stimulated in response to CD3/CD28 co-ligation or the combination of PMA and ionomycin, as well as the proliferation of primary murine T cells stimulated with PMA and ionomycin. A BC12 analog that lacks PDE7 inhibitory activity (BC12-4) displays similar biological activity, suggesting that BC12 does not act via PDE7 inhibition. To investigate the mechanism of inhibition of IL-2 production by BC12, we performed microarray analyses using unstimulated and stimulated Jurkat T cells in the presence or absence of BC12 or BC12-4. Our studies show these compounds affect the transcriptional response to stimulation and act via one or more shared targets to produce both anti-inflammatory and pro-stress effects. These results demonstrate potent immunomodulatory activity for BC12 and BC12-4 in T lymphocytes and suggest a potential clinical use as an immunotherapeutic to treat T lymphocyte-mediated diseases.
Departments of Biology, Boston College, Chestnut Hill, MA 02467, United States.
Chenjia
C
Xu
Departments of Biology, Boston College, Chestnut Hill, MA 02467, United States.
Arlene R
AR
Wyman
Departments of Biology, Boston College, Chestnut Hill, MA 02467, United States.
Manal A
MA
Alaamery
Departments of Biology, Boston College, Chestnut Hill, MA 02467, United States.
Shannon A
SA
Argueta
Departments of Biology, Boston College, Chestnut Hill, MA 02467, United States.
F Douglas
FD
Ivey
Hematology and Medical Oncology, Boston University Medical Center, Boston, MA 02118, United States.
John A
JA
Meyers
Hematology and Medical Oncology, Boston University Medical Center, Boston, MA 02118, United States.
Adam
A
Lerner
Departments of Biology, Boston College, Chestnut Hill, MA 02467, United States.
Tricia H
TH
Burdo
Departments of Biology, Boston College, Chestnut Hill, MA 02467, United States.
Timothy
T
Connolly
Departments of Biology, Boston College, Chestnut Hill, MA 02467, United States.
Charles S
CS
Hoffman
Departments of Biology, Boston College, Chestnut Hill, MA 02467, United States. Electronic address: chilest@bc.edu.
Thomas C
TC
Chiles
D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001463:Barbiturates / Q000737:chemistry / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D054708:Cyclic Nucleotide Phosphodiesterases, Type 7 / Q000037:antagonists & inhibitors; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D056747:Immunomodulation; D007376:Interleukin-2 / Q000235:genetics / Q000378:metabolism; D019169:Jurkat Cells; D008213:Lymphocyte Activation / Q000187:drug effects; D046228:Microarray Analysis; D013601:T-Lymphocytes / Q000187:drug effects* / Q000502:physiology
D000893:Anti-Inflammatory Agents; D001463:Barbiturates; D004791:Enzyme Inhibitors; D007376:Interleukin-2; D054708:Cyclic Nucleotide Phosphodiesterases, Type 7; C032232:barbituric acid
Cyclic nucleotide phosphodiesterase; Interleukin 2; Pro-inflammatory cytokines; T lymphocyte; Transcription factor