Neutrophil gelatinase B potentiates interleukin-8 tenfold by aminoterminalprocessing, whereas it degrades CTAP-III, PF-4, and GRO-alpha and leaves RANTES and MCP-2 intact

Chemokines are mediators in inflammatory and autoimmune disorders. Aminoter minal truncation of chemokines results in altered specific activities and r eceptor recognition patterns. Truncated forms of the CXC chemokine interleu kin (IL)-8 are more active than full-length IL-8 (1-77), provided the Glu-L eu-Arg (ELR) motif remains intact. Here, a positive feedback loop is demons trated between gelatinase B, a major secreted matrix metalloproteinase (MMP -9) from neutrophils, and IL-8, the prototype chemokine active on neutrophi ls. Natural human neutrophil progelatinase B was purified to homogeneity an d activated by stromelysin-1, Gelatinase B truncated IL-8(1-77) into IL-8(7 -77), resulting in a 10- to 27-fold higher potency in neutrophil activation , as measured by the increase in intracellular Ca++ concentration, secretio n of gelatinase B, and neutrophil chemotaxis. This potentiation correlated with enhanced binding to neutrophils and increased signaling through CXC ch emokine receptor-1 (CXCR1), but it was significantly less pronounced on a C XCRP-expressing cell line. Three other CXC chemokines-connective tissue-act ivating peptide-III (CTAP-III), platelet factor-4 (PF-4), and GRO-alpha-wer e degraded by gelatinase B. In contrast, the CC chemokines RANTES and monoc yte chemotactic protein-2 (MCP-2) were not digested by this enzyme. The obs ervation of differing effects of neutrophil gelatinase B on the proteolysis of IL-8 versus other CXC chemokines and on CXC receptor usage by processed IL-8 yielded insights into the relative activities of chemokines. This led to a better understanding of regulator (IL-8) and effector molecules (gela tinase B) of neutrophils and of mechanisms underlying leukocytosis, shock s yndromes, and stem cell mobilization by IL-8. (Blood. 2000;96: 2673-2681) ( C) 2000 by The American Society of Hematology.