The effect of synthetic LVV-hemorphin-4 (LVV-H4) on human blood and tonsils lymphocytes total phosphatase activity was studied by a spectrofluorimetric assay using 4-methylumbelliferyl phosphate (4-MUP) as a substrate. It has been established that LVV-H4 at concentrations of 10(-9) to 10(-7) M induces the inhibition of human blood (12-24%) and tonsils (42-45%) lymphocytes total phosphatase activity as 1 mM EGTA. The same peptide at concentrations of 10(-5) to 10(-4) M induces activation of human blood (48-57%) and tonsils (20-25%) lymphocytes total phosphatase activity. LVV-H4 is able to neutralize the inhibitory effect of calmodulin (CaM) antagonist and calcineurin inhibitor trifluoperazine (TFP) on human blood lymphocyte total phosphatase activity. It is suggested that a dose-dependent activation/inhibition of lymphocytes total phosphatase activity is due to activation/inhibition of lymphocyte calcineurin activity. Using enzyme-linked immunosorbentassay (ELISA) it was found that LVV-H4 neutralized the inhibitory effect of cyclosporin A (CsA) and TFP on interleukin-2 (IL-2) synthesis by activated blood lymphocytes. LVV-H4 also affects the lymphocytes proliferation, suppressed in pathophysiological condition, and restores their function by enhancement of DNA synthesis, as determined by measuring of [3H] thymidine incorporation into lymphocytes. It has been proposed that CaM is an essential component in starting up the molecular mechanism of hemorphins action and that calcineurin is a key enzyme underlying the molecular mechanism of hemorphins action on the brain and immune system.
The effect of synthetic LVV-hemorphin-7 and hemorphin-7 on hypothalamo-pituitary-adrenocortical axis activity in response to endotoxin-induced stress was studied. The intraperitoneal (ip) endotoxin (lipopolysaccaride, LPS) (0.5 mg/kg) administration in combination with hemorphin (1 mg/kg) induce significant decrease in plasma corticosterone and modest decrease in plasma levels of tumor necrosis factor-alpha (TNFalpha) in compare with elevated levels of both corticosterone and TNFalpha in plasma of rats received LPS administration alone. Increased activity of calcineurin in both plasma and brain of rats received ip administration of LPS, was recovered under LPS + hemorphin treatment. In two independent proteome analysis, using 2-dimensional fluorescence difference gel electrophoresis and the isotope coded protein label technology, peptidyl-prolyl cis-trans-isomerase A (cyclophilin A) was identified as regulated by hemorphins protein in mouse brain. A therapeutic potential of hemorphins and mechanisms of their homeostatic action in response to endotoxin-induced stress are discussed.
Biological activities of the multifunctional cytokine, interleukin-6 (IL-6) include stimulation of B cell proliferation, immunoglobulin production, and initiation of the acute-phase response. IL-6 affects the CNS in that it activates the hypothalamo-pituitary-adrenocortical (HPA) axis and increases brain tryptophan and serotonin metabolism. IL-6 has been proposed as an important mediator of interaction between the neuroendocrine and immune systems. The peripheral and central effects of IL-6 are presumably mediated through its membrane receptor (IL-6R). IL-6, IL-6R and their respective mRNAs have been detected in several brain regions. Although the functions of cytokines overlap considerably, each displays its own characteristic properties. Expression of IL-6 in the brain has been observed in several CNS disorders, some of which have been associated with disorders of serotonin metabolism. It is proposed that interactions between IL-6 and brain serotonin is a complex process which involves corticotropin-releasing factor (CRF) and opioid peptides. It is likely that the molecular mechanisms underlying the actions of IL-6 on the HPA axis and its other brain functions involve the integrated effects of glutamate, Ca2+, 3',5'-cyclic AMP, protein kinase C, and other metabolic pathways.
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