Circulating interleukin-6 induces fever through a STAT3-linked activation of COX-2 in the brain

2006 ◽  
Vol 291 (5) ◽  
pp. R1316-R1326 ◽  
Author(s):  
Christoph Rummel ◽  
Christelle Sachot ◽  
Stephen Poole ◽  
Giamal N. Luheshi
Keyword(s):  
Circumventricular Organs ◽  
Significant Rise ◽  
Infection And Inflammation ◽  
Normal Sheep Serum ◽  
Cox 2 ◽  
Rate Limiting ◽  
The Brain ◽  
Dependent Pathway ◽  
Nuclear Signal

Interleukin (IL)-6 is an important humoral mediator of fever following infection and inflammation and satisfies a number of criteria for a circulating pyrogen. However, evidence supporting such a role is diminished by the moderate or even absent ability of the recombinant protein to induce fever and activate the cyclooxygenase-2 (COX-2) pathway in the brain, a prerequisite step in the initiation and maintenance of fever. In the present study, we investigated the role of endogenous circulating IL-6 in a rodent model of localized inflammation, by neutralizing its action using a specific antiserum (IL-6AS). Rats were injected with LPS (100 μg/kg) or saline into a preformed air pouch in combination with an intraperitoneal injection of either normal sheep serum or IL-6AS (1.8 ml/rat). LPS induced a febrile response, which was accompanied by a significant rise in plasma IL-6 and nuclear STAT3 translocation in endothelial cells throughout the brain 2 h after treatment, including areas surrounding the sensory circumventricular organs and the median preoptic area (MnPO), important regions in mediating fever. These responses were abolished in the presence of the IL-6AS, which also significantly inhibited the LPS-induced upregulation of mRNA expression or immunoreactivity (IR) of the inducible form of COX, the rate-limiting enzyme for PGE2-synthesis. Interestingly, nuclear signal transducer and activator of transcription (STAT)3-positive cells colocalized with COX-2-IR, signifying that IL-6-activated cells are directly involved in PGE2 production. These observations suggest that IL-6 is an important circulating pyrogen that activates the COX-2-pathway in cerebral microvasculature, most likely through a STAT3-dependent pathway.

scholarly journals Interleukin (IL)-6, But Not IL-1, Induction in the Brain Downstream of Cyclooxygenase-2 Is Essential for the Induction of Febrile Response against Peripheral IL-1α

Endocrinology ◽  
2004 ◽  
Vol 145 (11) ◽  
pp. 5044-5048 ◽  
Author(s):  
Kyoko Kagiwada ◽  
Dai Chida ◽  
Tomoya Sakatani ◽  
Masahide Asano ◽  
Aya Nambu ◽  
...  
Keyword(s):  
Prostaglandin E2 ◽  
Cyclooxygenase 2 ◽  
Signaling Cascade ◽  
Endogenous Pyrogen ◽  
Febrile Response ◽  
Cox 2 ◽  
The Brain ◽  
Deficient Mice

Abstract IL-1 is an endogenous pyrogen produced upon inflammation or infection. Previously, we showed that, upon injection with turpentine, IL-1 is induced in the brain in association with the development of fever. The role of endogenous IL-1 in the brain and the signaling cascade to activate thermosensitive neurons, however, remain to be elucidated. In this report, febrile response was analyzed after peripheral injection of IL-1α. We found that a normal febrile response was induced even in IL-1α/β-deficient mice, indicating that production of IL-1 in the brain is not necessarily required for the response. In contrast, IL-6-deficient mice did not exhibit a febrile response. Cyclooxygenase (Cox)-2 expression in the brain was strongly induced 1.5 h after injection of IL-1α, whereas IL-6 expression was observed 3 h after the injection. Cox-2 expression in the brain was not influenced by IL-6 deficiency, whereas indomethacin, an inhibitor of cyclooxygenases, completely inhibited induction of IL-6. These observations suggest a mechanism of IL-1-induced febrile response in which IL-1 in the blood activates Cox-2, with the resulting prostaglandin E2 inducing IL-6 in the brain, leading to the development of fever.

scholarly journals TREM Receptors Connecting Bowel Inflammation to Neurodegenerative Disorders

Cells ◽  
2019 ◽  
Vol 8 (10) ◽  
pp. 1124 ◽  
Author(s):  
Gianfranco Natale ◽  
Francesca Biagioni ◽  
Carla Letizia Busceti ◽  
Stefano Gambardella ◽  
Fiona Limanaqi ◽  
...  
Keyword(s):  
Neurodegenerative Disorders ◽  
Potential Role ◽  
Intestinal Bacteria ◽  
Circumventricular Organs ◽  
Leaky Gut ◽  
Inflammatory Processes ◽  
Inflammatory Bowel ◽  
Disease Specificity ◽  
The Brain

Alterations in Triggering Receptors Expressed on Myeloid cells (TREM-1/2) are bound to a variety of infectious, sterile inflammatory, and degenerative conditions, ranging from inflammatory bowel disease (IBD) to neurodegenerative disorders. TREMs are emerging as key players in pivotal mechanisms often concurring in IBD and neurodegeneration, namely microbiota dysbiosis, leaky gut, and inflammation. In conditions of dysbiosis, compounds released by intestinal bacteria activate TREMs on macrophages, leading to an exuberant pro-inflammatory reaction up to damage in the gut barrier. In turn, TREM-positive activated macrophages along with inflammatory mediators may reach the brain through the blood, glymphatic system, circumventricular organs, or the vagus nerve via the microbiota-gut-brain axis. This leads to a systemic inflammatory response which, in turn, impairs the blood-brain barrier, while promoting further TREM-dependent neuroinflammation and, ultimately, neural injury. Nonetheless, controversial results still exist on the role of TREM-2 compared with TREM-1, depending on disease specificity, stage, and degree of inflammation. Therefore, the present review aimed to provide an update on the role of TREMs in the pathophysiology of IBD and neurodegeneration. The evidence here discussed the highlights of the potential role of TREMs, especially TREM-1, in bridging inflammatory processes in intestinal and neurodegenerative disorders.

scholarly journals The Role of Cyclooxygenase-2 in Cell Proliferation and Cell Death in Human Malignancies

2010 ◽  
Vol 2010 ◽  
pp. 1-21 ◽  
Author(s):  
Cyril Sobolewski ◽  
Claudia Cerella ◽  
Mario Dicato ◽  
Lina Ghibelli ◽  
Marc Diederich
Keyword(s):  
Cell Proliferation ◽  
Rate Limiting Step ◽  
Proliferation And Apoptosis ◽  
Cox 2 ◽  
Prostate Cancers ◽  
Cox 2 Inhibitors ◽  
Rate Limiting ◽  
Brain And Spinal Cord ◽  
Cox 1

It is well admitted that the link between chronic inflammation and cancer involves cytokines and mediators of inflammatory pathways, which act during the different steps of tumorigenesis. The cyclooxygenases (COXs) are a family of enzymes, which catalyze the rate-limiting step of prostaglandin biosynthesis. This family contains three members: ubiquitously expressed COX-1, which is involved in homeostasis; the inducible COX-2 isoform, which is upregulated during both inflammation and cancer; and COX-3, expressed in brain and spinal cord, whose functions remain to be elucidated. COX-2 was described to modulate cell proliferation and apoptosis mainly in solid tumors, that is, colorectal, breast, and prostate cancers, and, more recently, in hematological malignancies. These findings prompt us to analyze here the effects of a combination of COX-2 inhibitors together with different clinically used therapeutic strategies in order to further improve the efficiency of future anticancer treatments. COX-2 modulation is a promising field investigated by many research groups.

THE REGULATION OF MONOAMINE OXIDASE ACTIVITY BY ADRENAL CORTICAL STEROIDS

1973 ◽  
Vol 73 (3) ◽  
pp. 509-517 ◽  
Author(s):  
H. Parvez ◽  
S. Parvez
Keyword(s):  
Monoamine Oxidase ◽  
Significant Rise ◽  
Tissue Homogenate ◽  
Limiting Factor ◽  
Hydrocortisone Administration ◽  
Mao Activity ◽  
Rate Limiting ◽  
The Brain ◽  
Adrenalectomized Rats ◽  
Enzyme Monoamine Oxidase

ABSTRACT The activity of the enzyme monoamine oxidase (MAO) in the brain, heart, liver and spleen of rats 10 weeks after adrenalectomy was determined. Another group of adrenalectomized rats received 5 mg of hydrocortisone daily for the period of 10 days and their MAO activity was compared with that of control adrenalectomized rats. There was a significant rise in MAO activity following adrenalectomy in the tissue homogenate, mitochondrial and supernatant fractions of all the organs studied. Hydrocortisone administration decreased MAO activity to the level of normal rats. These results suggest that corticoids serve as a rate limiting factor for the activity of the enzyme MAO. This hypothesis was further tested in normal rats by blocking the biosynthesis of glucocorticoids with Metopirone®. Four hours after a single injection of 75 mg Metopirone the cerebral, hepatic and cardiac MAO showed marked increases from control levels. These results suggest that adrenal cortical steroids present in the circulation of normal animals regulate the activity of the enzyme MAO in most organs.

Impaired osmotic sensation in mice lacking TRPV4

2003 ◽  
Vol 285 (1) ◽  
pp. C96-C101 ◽  
Author(s):  
Atsuko Mizuno ◽  
Naoko Matsumoto ◽  
Masashi Imai ◽  
Makoto Suzuki
Keyword(s):  
Brain Slices ◽  
Free Water ◽  
Circumventricular Organs ◽  
Serum Osmolality ◽  
Cell Swelling ◽  
Free Water Clearance ◽  
Pass Through ◽  
The Brain ◽  
Negative Signal

The Ca2+-permeable cation channel TRPV4, which is part of the Trp family located in the circumventricular organs, is activated by cell swelling. To investigate the role of TRPV4 in osmotic sensation, we disrupted the TRPV4 gene in mice and examined the effect on osmotic metabolism. Disruption of the mouse TRPV4 gene did not influence either water intake behavior or serum osmolality. Short-term salt ingestion, however, seemed to impair the transient free water clearance. The level of serum arginine vasopressin (AVP) of TRPV4–/– mice was not significantly changed under normal conditions but was significantly increased under stimulated conditions. Incubation of brain slices with graded hyperosmolality suggested an exaggerated response of AVP secretion in TRPV4–/– mice. Thus TRPV4 in the brain may transmit a negative signal to AVP secretion similar to an inhibitory pass through the baroregulatory system. Thus, in the regulation of serum osmolality, TRPV4 is a swell-activated channel that appears to play a role in reversion toward hyposmolality.

The Role of Mitochondria in the Genesis of Neuroaxonal Dystrophy in the Brains of Aging Mice

1975 ◽  
Vol 33 ◽  
pp. 372-373
Author(s):  
J.E. Johnson
Keyword(s):  
Electron Microscopy ◽  
Present Report ◽  
Light And Electron Microscopy ◽  
Dorsal Column ◽  
Neuroaxonal Dystrophy ◽  
Nucleus Gracilis ◽  
Dystrophic Axons ◽  
The Brain ◽  
Nucleus Cuneatus

Although neuroaxonal dystrophy (NAD) has been examined by light and electron microscopy for years, the nature of the components in the dystrophic axons is not well understood. The present report examines nucleus gracilis and cuneatus (the dorsal column nuclei) in the brain stem of aging mice.Mice (C57BL/6J) were sacrificed by aldehyde perfusion at ages ranging from 3 months to 23 months. Several brain areas and parts of other organs were processed for electron microscopy.At 3 months of age, very little evidence of NAD can be discerned by light microscopy. At the EM level, a few axons are found to contain dystrophic material. By 23 months of age, the entire nucleus gracilis is filled with dystrophic axons. Much less NAD is seen in nucleus cuneatus by comparison. The most recurrent pattern of NAD is an enlarged profile, in the center of which is a mass of reticulated material (reticulated portion; or RP).

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