Amino-terminal processing of MIP-1beta/CCL4 by CD26/dipeptidyl-peptidase IV.
CD26 is a membrane-bound ectopeptidase with dipeptidyl peptidase IV (DPPIV) activity that has diverse functional properties in T cell physiology and in regulation of bioactive peptides. We have previously reported that activated human peripheral lymphocytes (PBL) secrete an amino-terminal truncated form of macrophage inflammatory protein (MIP)-1beta/(3-69) with novel functional specificity for CCR1, 2, and 5. In this report, we show that the full length MIP-1beta is processed by CD26/DPPIV to the truncated form and that cleavage can be blocked by DPPIV inhibitory peptides derived from HIV Tat(1-9) or the thromboxane A2 receptor, TAX2-R(1-9). Addition of Tat(1-9) or TAX2-R(1-9) peptides to PBL cultures partially blocks endogenous MIP-1beta processing. The kinetics of conversion of MIP-1beta from intact to MIP-1beta(3-69) in activated PBLs correlates with cell surface expression of CD26. Our results suggest that NH2-terminal processing of MIP-1beta and possibly other chemokines may depend on the balance between CD26/DPPIV enzymatic activity and cellular and viral proteins that modulate enzyme function.
Guan
Ennan
E
Division of Therapeutic Proteins, Center for Drug Evaluation and Research, Food and Drug Administration, Bethesda, Maryland 20892, USA. guan@cber.fda.gov
Wang
Jinhai
J
Norcross
Michael A
MA
D054407:Chemokine CCL4; D018819:Dipeptidyl Peptidase 4 / Q000032:analysis / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015696:Gene Products, tat / Q000494:pharmacology; D006801:Humans; D047468:Immunoprecipitation; D008214:Lymphocytes / Q000378:metabolism; D019402:Macrophage Inflammatory Proteins / Q000737:chemistry / Q000378:metabolism*; D013058:Mass Spectrometry; D009000:Monocytes / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism / Q000494:pharmacology; D010455:Peptides / Q000494:pharmacology; D044244:Receptors, Thromboxane A2, Prostaglandin H2 / Q000378:metabolism; D054322:tat Gene Products, Human Immunodeficiency Virus
D054407:Chemokine CCL4; D004791:Enzyme Inhibitors; D015696:Gene Products, tat; D019402:Macrophage Inflammatory Proteins; D010446:Peptide Fragments; D010455:Peptides; D044244:Receptors, Thromboxane A2, Prostaglandin H2; C494026:TAX2-R(1-9) protein, human; D054322:tat Gene Products, Human Immunodeficiency Virus; C415751:tat peptide (1-9), Human immunodeficiency virus 1; D018819:Dipeptidyl Peptidase 4