title: Piperine blocks interleukin-2-driven cell cycle progression in CTLL-2 T lymphocytes by inhibiting multiple signal transduction pathways.
abstract: Piperine, a pungent alkaloid found in the fruits of black pepper plants, has diverse physiological effects, including the ability to inhibit immune cell-mediated inflammation. Since the cytokine interleukin-2 (IL-2) is essential for the clonal expansion and differentiation of T lymphocytes, we investigated the effect of piperine on IL-2 signaling in IL-2-dependent mouse CTLL-2 T lymphocytes. Tritiated-thymidine incorporation assays and flow cytometric analysis of Oregon Green 488-stained cells showed that piperine inhibited IL-2-driven T lymphocyte proliferation; however, piperine did not cause T lymphocytes to die or decrease their expression of the high affinity IL-2 receptor, as determined by flow cytometry. Western blot analysis showed that piperine blocked the IL-2-induced phosphorylation of signal transducer and activator of transcription (STAT) 3 and STAT5 without affecting the upstream phosphorylation of Janus kinase (JAK) 1 and JAK3. In addition, piperine inhibited the IL-2-induced phosphorylation of extracellular signal-regulated kinase 1/2 and Akt, which are signaling molecules that regulate cell cycle progression. Piperine also suppressed the expression of cyclin-dependent kinase (Cdk) 1, Cdk4, Cdk6, cyclin B, cyclin D2, and Cdc25c protein phosphatase by IL-2-stimulated T lymphocytes, indicating G0/G1 and G2/M cell cycle arrest. Piperine-mediated inhibition of IL-2 signaling and cell cycle progression in CTLL-2 T lymphocytes suggests that piperine should be further investigated in animal models as a possible natural source treatment for T lymphocyte-mediated transplant rejection and autoimmune disease.
authors: Department of Pathology, Faculty of Medicine, Dalhousie University, Halifax, NS B3H 4R2, Canada.
authors: Carolyn D
authors: CD
authors: Doucette
authors: Department of Pathology, Faculty of Medicine, Dalhousie University, Halifax, NS B3H 4R2, Canada.
authors: Anna L
authors: AL
authors: Greenshields
authors: Department of Pathology, Faculty of Medicine, Dalhousie University, Halifax, NS B3H 4R2, Canada.
authors: Robert S
authors: RS
authors: Liwski
authors: Department of Pathology, Faculty of Medicine, Dalhousie University, Halifax, NS B3H 4R2, Canada; Department of Microbiology and Immunology, Faculty of Medicine, Dalhousie University Halifax, NS B3H 4R2, Canada; Department of Surgery, Faculty of Medicine, Dalhousie University Halifax, NS B3H 4R2, Canada. Electronic address: d.w.hoskin@dal.ca.
authors: David W
authors: DW
authors: Hoskin
mesh_terms: D000470:Alkaloids / Q000494:pharmacology*; D000818:Animals; D052117:Benzodioxoles / Q000494:pharmacology*; D015153:Blotting, Western; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D005434:Flow Cytometry; D007376:Interleukin-2 / Q000037:antagonists & inhibitors*; D053616:Janus Kinase 3 / Q000378:metabolism; D051379:Mice; D010766:Phosphorylation; D010880:Piperidines / Q000494:pharmacology*; D053284:Polyunsaturated Alkamides / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects*
chemical_list: D000470:Alkaloids; D052117:Benzodioxoles; D007376:Interleukin-2; D010880:Piperidines; D053284:Polyunsaturated Alkamides; D050796:STAT3 Transcription Factor; D050799:STAT5 Transcription Factor; C494087:Stat3 protein, mouse; C507935:Jak3 protein, mouse; D053616:Janus Kinase 3; D051057:Proto-Oncogene Proteins c-akt; D018844:Cyclin-Dependent Kinases; C008922:piperine
keywords: Akt; ERK1/2; IL-2; Piperine; STAT3; STAT5; T lymphocyte