In spite of this significantly decreased affinity for cognate ligand, 2D2 T cells effectively proliferated and produced cytokines

Revised and authorized the paper: KDE FB JM PBJ LH MS AK. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 8 September 2010 | Volume five | Challenge 9 | e12965 FLT-PET and Exp. Chemotherapy 33. Pfaffl MW A brand new mathematical model for relative quantification in realtime RT-PCR. Nucleic Acids Res 29: e45. 34. McDermott GM, Welch A, Employees RT, Gilbert FJ, Schweiger L, et al. Monitoring key breast cancer all through chemotherapy working with FDG-PET. Breast Cancer Res Treat 102: 7584. 35. Chang ZF, Huang DY, Hsue NC Differential phosphorylation of human thymidine kinase in proliferating and M phase-arrested human cells. J Biol Chem 269: 2124921254. 36. Munch-Petersen B, Cloos L, Jensen HK, Tyrsted G Human thymidine kinase 1. Regulation in standard and malignant cells. Adv Enzyme Regul 35: 6989. 9 September 2010 | Volume 5 | Situation 9 | e12965 Lipoic Acid Attenuates Inflammation through cAMP and Protein Kinase A Signaling Sonemany Salinthone1,2., Vijayshree Yadav1,two., Robynn V. Schillace1,two., Dennis N. Bourdette1,two, Daniel W. Carr1,3 1 Portland Veterans Affairs Health-related Center, Portland, Oregon, United states of america of America, 2 Division of Neurology, Oregon Wellness & Science University, Portland, Oregon, United states of America, three Division of Endocrinology, Oregon Health & Science University, Portland, Oregon, United states of America Abstract Background: Abnormal regulation of the inflammatory response is an important component of diseases such as diabetes, Alzheimer's disease and multiple sclerosis. Lipoic acid has been shown to have antioxidant and anti-inflammatory properties and is being pursued as a therapy for these diseases. We first reported that LA stimulates cAMP production by means of activation of G-protein coupled receptors and adenylyl cyclases. LA also suppressed NK cell activation and cytotoxicity. In this study we present evidence supporting the hypothesis that the anti-inflammatory properties of LA are mediated by the cAMP/PKA signaling cascade. Additionally, we show that LA oral administration elevates cAMP levels in MS subjects. Methodology/Principal Findings: We determined the effects of LA on IL-6, IL-17 and IL-10 secretion applying ELISAs. Treatment with 50 mg/ml and 100 mg/ml LA significantly reduced IL-6 levels by 19 and 34%, respectively, in T cell enriched PBMCs. IL-17 levels were also reduced by 35 and 50%, respectively. Though not significant, LA appeared to have a biphasic effect on IL-10 production. Thymidine incorporation studies showed LA inhibited T cell proliferation by 90%. T-cell activation was reduced by 50% as measured by IL-2 secretion. Western blot analysis showed that LA treatment increased phosphorylation of Lck, a downstream effector of protein kinase A. Pretreatment with a peptide inhibitor of PKA, PKI, blocked LA inhibition of IL-2 and IFN gamma production, indicating that PKA mediates these responses. Oral administration of 1200 mg LA to MS subjects resulted in increased cAMP levels in PBMCs four hours after ingestion. Average cAMP levels in 20 subjects were 43% higher than baseline. Conclusions/Significance: Oral administration of LA in vivo resulted in significant increases in cAMP concentration. The When shaping an immune response, both the TCR affinity and duration of antigen encounter play roles in directing the outcome of T cell activation antiinflammatory effects of LA are mediated in part by the cAMP/PKA signaling cascade. These novel findings enhance our understanding of the mechanisms of action of LA. Citation: Salinthon