Immune system chemokine activity

The key end result of TLR signalling is the induction of cytokines. Cytokines are proteins produced during an immune response that allow the maturation, activation and differentiation of effector cells in the immune system. The activation of NFkB and AP-1 by the MyD88 and the TREF dependent pathways leads to the production of proinflammatory cytokines such as IL-6, TNF-a and various chemokines. This pathway can also activate IRF-7 via TLR-7and TLR-9 allowing Type-I interferons to be produced. 

Chemokines are small chemotactic cytokines that act as important messenger molecules between cells of the immune system. Chemokines produce their effects by activating a family of G-protein-coupled receptors. Chemokine receptors are all seven-transmembrane glycoproteins that are structurally related. They may be characterized into those that bind to specific ligands, or those that bind several chemokine ligands. There are also virally encoded (viral) chemokine receptors that represent shared receptors that have been transduced into the viral genome during evolutionary history (Premack and SchaU 1996). 

It is well established that NF-kB signaling plays a critical role in inflammation and immunity. Understanding the mechanism of NF-kB involvement in opioid receptor activation and chemokine expression may provide a vital key to understanding this complex signaling network. However, the elucidation of molecular mechanisms following activation of the opioid receptor family could aid in the development of future therapeutics for immune system-related and inflammatory diseases, drug addiction and HIV infection. 

Opioid regulation of chemokine and chemokine receptor expression has several disease- related implications. Viral infection by HIV-1 can be enhanced with opioids that activate MOR while the opposite can be true for opioids that activate KOR. Increased levels of HIV-1 coreceptors, such as CCR5 and CXCR4, can promote viral binding and trafficking of HIV-1 virally infected cells. It is likely that this allows the viral disease to progress in the immune cells of the blood in addition to neurological reservoirs. Alterations of chemokine receptor expression will not only affect viral infection, but also alter immune system function. In certain diseases... 

The innate and the adaptive arms of the immune systems of higher organisms are bridged by a complex set of cellular and molecular mediators. The immunomodulatory activities of host defense peptides, such as the direct chemotactic activity, cytokine and chemokine induction, and the stimulation of differentiation and activation of effector cells, may contribute to this process. Host defense peptides may also influence the polarization of adaptive immune response, for example, through their effects on cytokine production. ... 

The most important clinical application of glucocorticoids and their semisynthetic analogs is their anti-inflammatory activity, discovered in 1949 by Hench and co-workers. The profound anti-inflammatory effects of glucocorticoids arise from the combined effects of these steroids on both the cellular and molecular mediators of inflammation these effects are separate from the metabolic effects described above and further indication of the widespread diversity of macromolecules to which steroids can bind. Glucocorticoids suppress inflammation at the cellular level by downregulating the concentration, distribution, and function of leukocytes (white blood cells) that profoundly influence inflammation and response to infection within the body (In this way, steroids help to mediate the overlap between the endocrine systems [chapter 5] and the immune systems [chapter 6]). Glucocorticoids also suppress inflammation at the molecule level by suppressing inflammatory cytokines, chemokines, and other molecular mediators of inflammation. 

There is also one unknown parameter regarding the use of HuCNS-SCs for therapy that has not been addressed in preclinical studies so far. Most of the studies were performed in immunosuppressed rats or NOD/SCID mice. Therefore, the activity of cytokines and chemokines of the immune system and their potential risks on HuCNS-SC therapy have not been fully investigated. Stem cells, including neurospheres, respond to the expression and activities of cytokines and chemokines. These activities may have adverse effects on the survival, migration and differentiation of HuCNS-SCs and thus affect their potential therapeutic use. 

Cytokines are a heterogenous group of polypeptide mediators that have been associated with activation of numerous functions, including the immune system and inflammatory responses. The cytokine families include, but are not limited to, interleukins, chemokines, tumor necrosis factors, interferons (INF-a, -0, and -y), colony-stimulating factors, growth factors, neuropoietins, and neurotrophins (see Table 13.4). 

The activation, maturation, differentiation, and mobilization of immune cells are controlled by cytokines (e.g., interleukins, interferons, and chemokines), which are soluble mediators produced by immune cells and/or by cells outside the immune system (e.g., epithelial cells and cells of the nervous system). Other soluble (humoral) mediators produced by immune cells include antibodies (immunoglobulins) and complement proteins (plasma proteins produced by monocytes and macrophages as well as hepatocytes). Mediators are important in the implementation and regulation of immune responses. 

MDD. Activation of some aspects of the immune system is generally associated with MDD, even in patients who are otherwise quite healthy. Many studies support this idea (Raison et al., 2006). Proinflammatory cytokines, such as IL-6 and TNF-a, are increased in plasma and in the CNS. There also are increases in the level of chemokines and adhesion molecules. 

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