CYCLOSPORINE-H IS A POTENT AND SELECTIVE FORMYL PEPTIDE RECEPTOR ANTAGONIST - COMPARISON WITH L-L-LEUCYL-L-PHENYLALANYL-L-LEUCYL-L-PHENYLALANINE AND CYCLOSPORINE-A, CYCLOSPORINE-B, CYCLOSPORINE-C, CYCLOSPORINE-D, AND CYCLOSPORINE-E

The cyclic undecapeptide, cyclosporin (Cs) H, is a potent inhibitor of FMLP-induced superoxide anion (O2-) formation in human neutrophils. W e studied the effects of CsH in comparison with those of l-L-leucyl-L- phenylalanyl-L-leucyl-L-phenylalanine (BocPLPLP), a well known formyl peptide receptor antagonist, and of other Cs on activation of N6,2'-O- dibutyryl adenosine 3:5'-monophosphate differentiated HL-60 cells and human erythroleukemia cells (HEL cells). CsH inibited FMLP binding in HL-60 membranes with a K(i) (inhibition constant) of 0.10 muM. CsH inh ibited activation by FMLP of high affinity GTPase (the enzymatic activ ity of alpha-subunits of heterotrimeric regulatory guanine nucleotide- binding proteins) in HL-60 membranes with a K(i) of 0.79 muM. CsH inhi bited the stimulatory effects of FMLP on cytosolic Ca2+ concentration ([Ca2+]1), O2- formation, and beta-glucuronidase release with K(i) val ues of 0.08, 0.24, and 0.45 muM, respectively. BocPLPLP was 14-fold le ss potent than CsH in inhibiting FMLP binding and 4- to 6-fold less po tent than CsH in inhibiting FMLP-induced GTP hydrolysis, rises in [Ca2 +]i, O2- formation, and beta-glucuronidase release. CsA reduced FMLP-i nduced O2- formation by 20%, but CsB, CsC, CsD, and CsE did not. CsA, CsB, CsC, CsD, and CsE did not affect FMLP-induced rises in [Ca2+]i. B ocPLPLP inhibited leukotriene B4-induced rises in [Ca2+]i with a K(i) of 0.33 muM, whereas CsH showed no inhibitory effect. CsH and BocPLPLP did not inhibit the rises in (Ca2+]i induced by several other stimuli in HL-60 cells and HEL cells. Our results show that 1) CsH is a more potent formyl peptide receptor antagonist than BocPLPLP;2) unlike BocP LPLP, CsH is selective; and 3) N-methyl-D-valine which is present at p osition 11 of the amino acid sequence of CsH but not of other Cs is cr ucial for FMLP antagonism.