Other affiliations: Memorial Sloan Kettering Cancer Center, Rockefeller University, University of Calgary ...read more
Bio: Carl Nathan is an academic researcher from Cornell University. The author has contributed to research in topic(s): Nitric oxide synthase & Mycobacterium tuberculosis. The author has an hindex of 135, co-authored 430 publication(s) receiving 91535 citation(s). Previous affiliations of Carl Nathan include Memorial Sloan Kettering Cancer Center & Rockefeller University.
Topics: Nitric oxide synthase, Mycobacterium tuberculosis, Macrophage, Nitric oxide, Tumor necrosis factor alpha
Carl Nathan1•Institutions (1)
TL;DR: How different forms of nitric oxide synthase help confer specificity and diversity on the effects of this remarkable signaling molecule is reviewed.
Abstract: Evolution has resorted to nitric oxide (NO), a tiny, reactive radical gas, to mediate both servoregulatory and cytotoxic functions. This article reviews how different forms of nitric oxide synthase help confer specificity and diversity on the effects of this remarkable signaling molecule.
TL;DR: Although the high-output NO pathway probably evolved to protect the host from infection, suppressive effects on lymphocyte proliferation and damage to other normal host cells confer upon NOS2 the same protective/destructive duality inherent in every other major component of the immune response.
Abstract: ▪ Abstract At the interface between the innate and adaptive immune systems lies the high-output isoform of nitric oxide synthase (NOS2 or iNOS). This remarkable molecular machine requires at least 17 binding reactions to assemble a functional dimer. Sustained catalysis results from the ability of NOS2 to attach calmodulin without dependence on elevated Ca2+. Expression of NOS2 in macrophages is controlled by cytokines and microbial products, primarily by transcriptional induction. NOS2 has been documented in macrophages from human, horse, cow, goat, sheep, rat, mouse, and chicken. Human NOS2 is most readily observed in monocytes or macrophages from patients with infectious or inflammatory diseases. Sustained production of NO endows macrophages with cytostatic or cytotoxic activity against viruses, bacteria, fungi, protozoa, helminths, and tumor cells. The antimicrobial and cytotoxic actions of NO are enhanced by other macrophage products such as acid, glutathione, cysteine, hydrogen peroxide, or superoxid...
TL;DR: The next ten years will bring forth evidence that NO is produced in slime molds, locusts, beetles, horseshoe crabs, mollusks, chickens, mice, rats, cows, and humans, and its physiologic roles will be at least as protean as those discovered for corticosteroids in the 194Os- 1980s.
Abstract: Carl Nathan and Qiao-wen Xie Beatrice and Samuel Seaver Laboratory Department of Medicine Cornell University Medical College New York, New York 10021 Imagine it’s 1985. You’ve joined an environmentally con- scious friend at a sidewalk cafe. Your companion is irked that traffic has fouled the air with nitric oxide (NO). Be- cause your imagination was piqued by a paper in the Pro- ceedings of the National Academy of Sciences reporting inorganic nitrite production by activated macrophages (StuehrandMarietta, 1985),youcounteryourfriend’scom- plaint with a prediction that the next ten years will bring forth evidence that NO is produced in slime molds, locusts, beetles, horseshoe crabs, mollusks, chickens, mice, rats, cows, and humans (Eiphick et al., 1993; Geiperin, 1994; Lee et al., 1994; Nathan and Xie, 1994; Werner-Feimayer et al., 1994). if so, your friend retorts, this would be no more than eukaryotic smog, a waste product of L-arginine metabolism. You concede that L-arginine-derived NO and its oxidation products will be excreted in people’s saliva, breath, and urine, but you insist NO is an autacoid, not a byproduct. Its physiologic roles will be at least as protean as those discovered for corticosteroids in the 194Os- 1980s and eicosanoids in the 196Os-198Os- ail three the products of hemecontaining oxygenases. You speculate that NO will regulate the following: tran- scription factor activation; translation of mRNAs controi- ling Fe metabolism; mutagenesis; apoptosis; giycolysis and mitochondriai electron transport; protein acyiation; deoxynucieotide synthesis; fusion of myObiaSt8; adhesion of platelets and neutrophiis; proliferation of myeloid pro- genitors T cells, keratinocytes, and tumor ceils; release of pituitary hormones; the tone of bronchi and sphincters; the contractions of
TL;DR: Testing as a sole agent, IFN-gamma was the only one of the 12 cytokines capable of inducing both NO2- and H2O2 release and the pathways leading to secretion of H2 O2 and No2- are independent.
Abstract: The capacity of 12 cytokines to induce NO2- or H2O2 release from murine peritoneal macrophages was tested by using resident macrophages, or macrophages elicited with periodate, casein, or thioglycollate broth. Elevated H2O2 release in response to PMA was observed in resident macrophages after a 48-h incubation with IFN-gamma, TNF-alpha, TNF-beta, or CSF-GM. Of these, only IFN-gamma induced substantial NO2- secretion during the culture period. The cytokines inactive in both assays under the conditions tested were IL-1 beta, IL-2, IL-3, IL-4, IFN-alpha, IFN-beta, CSF-M, and transforming growth factor-beta 1. Incubation of macrophages with IFN-gamma for 48 h in the presence of LPS inhibited H2O2 production but augmented NO2- release, whereas incubation in the presence of the arginine analog NG-monomethylarginine inhibited NO2- release but not H2O2 production. Although neither TNF-alpha nor TNF-beta induced NO2- synthesis on its own, addition of either cytokine together with IFN-gamma increased macrophage NO2- production up to six-fold over that in macrophages treated with IFN-gamma alone. Moreover, IFN-alpha or IFN-beta in combination with LPS could also induce NO2- production in macrophages, as was previously reported for IFN-gamma plus LPS. These data suggest that: 1) tested as a sole agent, IFN-gamma was the only one of the 12 cytokines capable of inducing both NO2- and H2O2 release; 2) the pathways leading to secretion of H2O2 and NO2- are independent; 3) either IFN-gamma and TNF-alpha/beta or IFN-alpha/beta/gamma and LPS can interact synergistically to induce NO2- release.
28 Jul 2005
TL;DR: Attention is focussed on the ROS/RNS-linked pathogenesis of cancer, cardiovascular disease, atherosclerosis, hypertension, ischemia/reperfusion injury, diabetes mellitus, neurodegenerative diseases, rheumatoid arthritis, and ageing.
Abstract: Reactive oxygen species (ROS) and reactive nitrogen species (RNS, e.g. nitric oxide, NO(*)) are well recognised for playing a dual role as both deleterious and beneficial species. ROS and RNS are normally generated by tightly regulated enzymes, such as NO synthase (NOS) and NAD(P)H oxidase isoforms, respectively. Overproduction of ROS (arising either from mitochondrial electron-transport chain or excessive stimulation of NAD(P)H) results in oxidative stress, a deleterious process that can be an important mediator of damage to cell structures, including lipids and membranes, proteins, and DNA. In contrast, beneficial effects of ROS/RNS (e.g. superoxide radical and nitric oxide) occur at low/moderate concentrations and involve physiological roles in cellular responses to noxia, as for example in defence against infectious agents, in the function of a number of cellular signalling pathways, and the induction of a mitogenic response. Ironically, various ROS-mediated actions in fact protect cells against ROS-induced oxidative stress and re-establish or maintain "redox balance" termed also "redox homeostasis". The "two-faced" character of ROS is clearly substantiated. For example, a growing body of evidence shows that ROS within cells act as secondary messengers in intracellular signalling cascades which induce and maintain the oncogenic phenotype of cancer cells, however, ROS can also induce cellular senescence and apoptosis and can therefore function as anti-tumourigenic species. This review will describe the: (i) chemistry and biochemistry of ROS/RNS and sources of free radical generation; (ii) damage to DNA, to proteins, and to lipids by free radicals; (iii) role of antioxidants (e.g. glutathione) in the maintenance of cellular "redox homeostasis"; (iv) overview of ROS-induced signaling pathways; (v) role of ROS in redox regulation of normal physiological functions, as well as (vi) role of ROS in pathophysiological implications of altered redox regulation (human diseases and ageing). Attention is focussed on the ROS/RNS-linked pathogenesis of cancer, cardiovascular disease, atherosclerosis, hypertension, ischemia/reperfusion injury, diabetes mellitus, neurodegenerative diseases (Alzheimer's disease and Parkinson's disease), rheumatoid arthritis, and ageing. Topics of current debate are also reviewed such as the question whether excessive formation of free radicals is a primary cause or a downstream consequence of tissue injury.
Richard O. Hynes1•Institutions (1)
TL;DR: There is growing evidence that aging involves, in addition, progressive changes in free radical-mediated regulatory processes that result in altered gene expression.
Abstract: At high concentrations, free radicals and radical-derived, nonradical reactive species are hazardous for living organisms and damage all major cellular constituents. At moderate concentrations, how...
Author's H-index: 135