Proinflammatory cytokines functions

TNF is a pleiotropic cytokine exerting a wide range of cellular responses, that affect biological processes such as lipid metabolism, coagulation, and insulin resistance and the function of endothelial cells. As a major proinflammatory cytokine TNF is also involved in progression of diseases like cancer, Alzheimer, Diabetes type II, cardiovascular, pulmonary or neurological disorders, and many autoimmune diseases. Blocking the action of TNF clearly reduces its inflammatory potential on various autoimmune disorders like Crohn s disease, rheumatoid arthritis (RA), and psoriasis. 

Gene regulation by tocopherols has mainly been associated with PKC because of its deactivation by a-tocopherol and its contribution in the regulation of a number of transcription factors (NF-kappaB, API). A direct participation of the pregnane X receptor (PXR)/ retinoid X receptor (RXR) has been also shown. The antioxidant-responsive element (ARE) and the TGF-beta-responsive element appear in some cases to be implicated as well. The obser ved immunmodulatory function of a-tocopherol may also be attributed to the fact that the release of the proinflammatory cytokine interlukin-l 3 can be inhibited by a-tocopherol via... 

El4. Ertel, E., Keel,M Steckholzer, U.,Ungethum, U andTrentz, O., Interleukin-10 attenuates the release of proinflammatory cytokines but depresses splenocyte functions in murine endotox-emia. Arch. Surg. 131, 51-56 (1996). 

Histamine contributes to the progression of allergic-inflammatory responses by enhancement of the secretion of proinflammatory cytokines like IL-la, IL-1(3, IL-6 as well as chemokines like RANTES or IL-8, both in several cell types and local tissues [26-29]. Endothelial cells express functional HRl and HR2 and increased adhesion molecule expression such as ICAM-1, VCAM-1 and P-selectin was demonstrated by histamine infusion via HRl [30-32]. Histamine regulates the expression of its own receptors on endothelial cells and influences the overall inflammatory reaction [33]. 

IF-18 is another proinflammatory cytokine which can support Th-1 responses [24]. Keratinocytes functionally respond to IL-18 with upregulation of MHC I, reinforcement of the IFN-y-induced MHC class II expression and production of the Th-1 attracting chemokine CXCLIO [25]. This supports the notion that IL-18 is involved in the pathogenesis of local Th-1 responses in chronic inflammatory skin diseases. 

Histamine actively participates in functions and activity of DC precursors as well as their immature and mature forms. Immature and mature DCs express all four HRs [179-182]. In the differentiation process of type 1 DC from monocytes, HRl and HR3 act as positive stimulants that increase antigen-presentation capacity and proinflammatory cytokine production and Thl-priming activity. In contrast, HR2 acts as a suppressive molecule for antigen-presentation capacity, enhances IL-10 production and induces of IL-lO-producing T cells [183-185]. 

There are several mechanisms whereby antidepressants can modify intracellular events that occur proximal to the posts)maptic receptor sites. Most attention has been paid to the actions of antidepressants on those pathways that are controlled by receptor-coupled second messengers (such as cyclic AMP, inositol triphosphate, nitric oxide and calcium binding). However, it is also possible that chronic antidepressant treatment may affect those pathways that involve receptor interactions with protein tyrosine kinases, by increasing specific growth factor synthesis or by regulating the activity of proinflammatory cytokines. These pathways are particularly important because they control many aspects of neuronal function that ultimately underlie the ability of the brain to adapt and respond to pharmacological and environmental stimuli. One mechanism whereby antidepressants could increase the s)mthesis of trophic factors is... 

Methotrexate s principal mechanism of action at the low doses used in the rheumatic diseases probably relates to inhibition of aminoimidazolecarboxamide ribonucleotide (AICAR) transformylase and thymidylate synthetase, with secondary effects on polymorphonuclear chemotaxis. There is some effect on dihydrofolate reductase and this affects lymphocyte and macrophage function, but this is not its principal mechanism of action. Methotrexate has direct inhibitory effects on proliferation and stimulates apoptosis in immune-inflammatory cells. Additionally, inhibition of proinflammatory cytokines linked to rheumatoid synovitis has been shown, leading to decreased inflammation seen with rheumatoid arthritis. 

There is some evidence that adenosine also participates in modulating peripheral somatosensory function through A3 receptors on immune cells. A predominant response to the activation of A3 receptors is degranulation of mast cells causing the release of multiple proinflammatory mediators (IL-6/IL-10/IL-12). Further involvement of A3 receptors in pain and inflammation may be a result of adenosine-mediated inhibition of the release of tumor necrosis factor a (TNF-a), a proinflammatory cytokine produced by monocytes and macrophages. 

Proinflammatory cytokines, released by activated macrophages and monocytes during infection, can act on neural targets that control thermogenesis, behavior, and mood. In addition to induction of fever, cytokines induce other biological functions associated with the acute-phase response, including hypophagia and sleep. Cytokine production has been detected within the central nervous... 

Glia Proinflammatory Cytokine Upregulation as a Therapeutic Target for Neurodegenerative Diseases Function-Based and Target-Based Discovery Approaches... 

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