Distinct and Nonredundant In Vivo Functions of TNF Produced by T Cells and Macrophages/NeutrophilsProtective and Deleterious Effects

Grivennikov, Sergei Si; Tumanov, Alexei V.; Liepinsh, Dmitry J.; Kruglov, Andrey; Marakusha, B.I.; An, Shakhov; Murakami, Takaya; Drutskaya, Ludmila N.; Förster, Irmgard; Clausen, Björn E.

doi:10.1016/s1074-7613(04)00379-6

Cited by 66 publications

(84 citation statements)

References 4 publications

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“…It was previously shown that IL-1, IL-6, and TNF-␣ are critically required to trigger a normal response to Listeria monocytogenes challenge (6,11,13,26,28). The possibility that the phenotype of cyclin D3-null mice was caused by insufficient cytokine levels was ruled out by the observations that the levels of these cytokines were elevated in Listeria-infected cyclin D3-null mice compared to those of their infected wild-type counterparts (IL-1␤, 40.39 Ϯ 18.56 pg/ml versus 31.53 Ϯ 12.01 pg/ml; IL-6, 579.25 Ϯ 60.08 pg/ml versus 62.21 Ϯ 2.41 pg/ml; TNF-␣, 372.28 Ϯ 25.91 pg/ml versus 86.54 Ϯ 35.21 pg/ml; values represent means Ϯ standard deviations).…”

Section: Resultsmentioning

confidence: 99%

Essential Role for Cyclin D3 in Granulocyte Colony-Stimulating Factor-Driven Expansion of Neutrophil Granulocytes

Sicińska

Lee

Gits

et al. 2006

Molecular and Cellular Biology

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The proliferation of neutrophil granulocyte lineage is driven largely by granulocyte colony-stimulating factor (G-CSF) acting via the G-CSF receptors. In this study, we show that mice lacking cyclin D3, a component of the core cell cycle machinery, are refractory to stimulation by the G-CSF. Consequently, cyclin D3-null mice display deficient maturation of granulocytes in the bone marrow and have reduced levels of neutrophil granulocytes in their peripheral blood. The mutant mice are unable to mount a normal response to bacterial challenge and succumb to microbial infections. In contrast, the expansion of hematopoietic stem cells and lineage-committed myeloid progenitors proceeds relatively normally in mice lacking cyclin D3, revealing that the requirement for cyclin D3 function operates at later stages of neutrophil development. Importantly, we verified that this requirement is specific to cyclin D3, as mice lacking other G 1 cyclins (D1, D2, E1, or E2) display normal granulocyte counts. Our analyses revealed that in the bone marrow cells of wild-type mice, activation of the G-CSF receptor leads to upregulation of cyclin D3. Collectively, these results demonstrate that cyclin D3 is an essential cell cycle recipient of G-CSF signaling, and they provide a molecular link of how G-CSF-dependent signaling triggers cell proliferation.

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Section: Resultsmentioning

confidence: 99%

Essential Role for Cyclin D3 in Granulocyte Colony-Stimulating Factor-Driven Expansion of Neutrophil Granulocytes

Sicińska

Lee

Gits

et al. 2006

Molecular and Cellular Biology

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“…Muscarinic receptors are expressed on immune cells, including macrophages (15,31,32), which produce TNF during endotoxemia (33,34). Vagal efferents, distributed throughout the reticuloendothelial system and other peripheral organs are positioned to rapidly transmit the antiinflammatory signal to these cells.…”

Section: Discussionmentioning

confidence: 99%

Central muscarinic cholinergic regulation of the systemic inflammatory response during endotoxemia

Pavlov

Ochani

Gallowitsch-Puerta

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

296

212

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TNF has a critical mediator role in inflammation and is an important therapeutic target. We recently discovered that TNF production is regulated by neural signals through the vagus nerve. Activation of this ''cholinergic antiinflammatory pathway'' inhibits the production of TNF and other cytokines and protects animals from the inflammatory damage caused by endotoxemia and severe sepsis. Here, we describe a role for central muscarinic acetylcholine receptors in the activation of the cholinergic antiinflammatory pathway. Central muscarinic cholinergic activation by muscarine, the M1 receptor agonist McN-A-343, and the M2 receptor antagonist methoctramine inhibited serum TNF levels significantly during endotoxemia. Centrally administered methoctramine stimulated vagus-nerve activity measured by changes in instantaneous heart-rate variability. Blockade of peripheral muscarinic receptors did not abolish antiinflammatory signaling through the vagus nerve, indicating that peripheral muscarinic receptors on immune cells are not required for the cytokine-regulating activities of the cholinergic antiinflammatory pathway. The role of central muscarinic receptors in activating the cholinergic antiinflammatory pathway is of interest for the use of centrally acting muscarinic cholinergic enhancers as antiinflammatory agents. muscarinic receptors ͉ systemic inflammation ͉ TNF ͉ vagus nerve T he overproduction of cytokines, including TNF, mediates tissue damage during the response to injury or pathogenic invasion (1). Physiological and molecular mechanisms that control TNF production maintain cytokine homeostasis and minimize or prevent damage during the host response to infection, injury, arthritis, and other disorders (1-3). Recently, we found (4-6) that electrical or pharmacological activation of the efferent vagus nerve inhibits the release of TNF and attenuates the development of endotoxin-induced shock in rodents. Stimulation of the efferent vagus nerve activates the release of acetylcholine. Although the vagus nerve is a ''classical'' cholinergic regulator of visceral functions in which peripheral muscarinic acetylcholine receptors have a major mediating role, the vagusnerve cytokine-inhibiting activity (which is termed ''the cholinergic antiinflammatory pathway'') requires signaling through nicotinic ␣ 7 subunit-containing receptors (4, 5).Studies have implicated muscarinic receptor-dependent mechanisms in the central modulation and integration of vagal regulation of visceral functions. For example, vagus nerve control of glycogen synthesis in the liver, the Bezold-Jarish cardiovascular reflex and the regulation of exocrine pancreatic secretion are modulated centrally by brain muscarinic receptor mechanisms (7-10). Thus, we reasoned that brain muscarinic receptors could be involved in the central regulation of the vagus-nerve immunomodulatory function. Our results indicate that central cholinergic activation by selective muscarinic receptor ligands significantly inhibits systemic TNF in endotoxemic rats and activates th...

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“…In another model which is known to be largely dependent on TNF produced by T cells and macrophages/neutrophils (21), not only LT␣ ⌬/⌬ but also conventional LT␣ Ϫ/Ϫ mice were able to develop hepatitis after intravenous administration of a relatively high dose of concanavalin A (18 mg/kg) (data not shown). At a lower concanavalin A dose (9 mg/kg), LT␣ Ϫ/Ϫ mice showed a trend towards decreased TNF mRNA expression in their livers 1 hour after the injection (see Fig.…”

Section: Tnf Production In Vivo In Response To Lps Is Normal In the Lt␣mentioning

confidence: 98%

Novel Lymphotoxin Alpha (LTα) Knockout Mice with Unperturbed Tumor Necrosis Factor Expression: Reassessing LTα Biological Functions

Liepinsh

Grivennikov

Klarmann

et al. 2006

Molecular and Cellular Biology

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Distinct and Nonredundant In Vivo Functions of TNF Produced by T Cells and Macrophages/NeutrophilsProtective and Deleterious Effects

Cited by 66 publications

References 4 publications

Essential Role for Cyclin D3 in Granulocyte Colony-Stimulating Factor-Driven Expansion of Neutrophil Granulocytes

Essential Role for Cyclin D3 in Granulocyte Colony-Stimulating Factor-Driven Expansion of Neutrophil Granulocytes

Central muscarinic cholinergic regulation of the systemic inflammatory response during endotoxemia

Novel Lymphotoxin Alpha (LTα) Knockout Mice with Unperturbed Tumor Necrosis Factor Expression: Reassessing LTα Biological Functions

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