LVV-hemorphin-4 modulates Ca2+/calmodulin-dependent pathways in the immune system by the same mechanism as in the brain.

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.