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Dr. Gerald Weissmann, professor emeritus at New York University School of Medicine, a long-standing member of the American Society for Clinical Investigation, and a former president of the American College [...]

T cell receptor (TCR)--dependent regulatory T ceil ([T.sub.reg]) activity controls effector T cell ([T.sub.eff]) function and is inhibited by the inflammatory cytokine tumor necrosis factor--[alpha] (TNF-[alpha]). Protein kinase C-[theta] (PKC-[theta]) recruitment to the immunological synapse is required for full [T.sub.eff] activation. In contrast, PKC-[theta] was sequestered away from the [T.sub.reg] immunological synapse. Furthermore, PKC-[theta] blockade enhanced [T.sub.reg] function, demonstrating PKC-[theta] inhibits [T.sub.reg]-mediated suppression. Inhibition of PKC-[theta] protected [T.sub.reg] from inactivation by TNF-[alpha], restored activity of defective [T.sub.reg] from rheumatoid arthritis patients, and enhanced protection of mice from inflammatory colitis. [T.sub.reg] freed of PKC-[theta]--mediated inhibition can function in the presence of inflammatory cytokines and thus have therapeutic potential in control of inflammatory diseases. 10.1126/science.1186068

Tetracyclines have recently been shown to have 'chondroprotective' effects in inflammatory arthritides in animal models. Since nitric oxide (NO) is spontaneously released from human cartilage affected by osteoarthritis (OA) or rheumatoid arthritis in quantities sufficient to cause cartilage damage, we evaluated the effect of tetracyclines on the expression and function of human OA-affected nitric oxide synthase (OA-NOS) and rodent inducible NOS (iNOS). Among the tetracycline group of compounds, doxycycline > minocycline blocked and reversed both spontaneous and interleukin 1[Beta]-induced OA-NOS activity in ex vivo conditions. Similarly, minocycline [greater than or equal to] doxycycline inhibited both lipopolysaccharide- and interferon-[Gamma]-stimulated iNOS in RAW 264.7 cells in vitro, as assessed by nitrite accumulation. Although both these enzyme isoforms could be inhibited by doxycycline and minocycline, their susceptibility to each of these drugs was distinct. Unlike acetylating agents or competitive inhibitors of L-arginine that directly inhibit the specific activity of NOS, doxycycline or minocycline has no significant effect on the specific activity of iNOS in cell-free extracts. The mechanism of action of these drugs on murine iNOS expression was found to be, at least in part, at the level of RNA expression and translation of the enzyme, which would account for the decreased iNOS protein and activity of the enzyme. Tetracyclines had no significant effect on the levels of mRNA for [Beta]-actin and glyceraldehyde-3-phosphate dehydrogenase nor on levels of protein of [Beta]-actin and cyclooxygenase 2 expression. These studies indicate that a novel mechanism of action of tetracyclines is to inhibit the expression of NOS. Since the overproduction of NO has been implicated in the pathogenesis of arthritis, as well as other inflammatory diseases, these observations suggest that tetracyclines should be evaluated as potential therapeutic modulators of NO for various pathological conditions.

Nitric oxide synthesized by inducible nitric oxide synthase is thought to reduce inflammation in rheumatic and autoimmune illnesses. The exposure of lipopolysaccharide-induced murine macrophages to therapeutic concentrations of aspirin and hydrocortisone suppressed the expression of iNOS and the generation of nitrite. This suppression of inducible nitric oxide synthase (iNOS) expression and role shows another process of action for aspirin, if not for all aspirin-like drugs. The impact is applied at the degree of translational/ posttranslational changes and directly on the catalytic activity of iNOS.

Extracellular nitric oxide results with intracellular glutathione to form nitrosylated adduct and activator, hexose monophosphate shunt (HMPS). The effects of nitric oxide on glucose metabolism and oxidant production in human neutrophils is studied. S-nitrosoglutathione functions as a stable intracellular intermediate of nitric oxide activity and protects against nitric oxide-dependent cytotoxicity.

It greatly concerns us that the reputation of one of our faculty, cancer-vaccine researcher Nina Bhardwaj, was called publicly into question through your premature publication of fired researcher David O'Neill's [...]