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 I:1-77), provided the Glu- Leu-Arg (ELR) motif remains intact. Here, a positive feedback loop is demon strated between gelatinase B, a major secreted matrix metalloproteinase (MM P-9) from neutrophils, and IL-8, the prototype chemokine active on neutroph ils. Natural human neutrophil progelatinase B was purified to homogeneity a nd activated by stromelysin-l. Gelatinase B truncated IL-8(1-77) into IL-8( 7-77), resulting in a 10- to 27-fold higher potency in neutrophil activatio n, as measured by the increase in intracellular Ca++ concentration, secreti on of gelatinase B, and neutrophil chemotaxis. This potentiation correlated with enhanced binding to neutrophils and increased signaling through CXC c hemokine receptor-1 (CXCR1), but it was significantly less pronounced on a CXCR2-expressing cell line. Three other CXC chemokines-connective tissue-ac tivating peptide-ill (CTAP-III), platelet factor-4 (PF-4), and GRO-alpha- w ere degraded by gelatinase B. In contrast, the CC chemokines RANTES and mon ocyte chemotactic protein-2 (MCP-P) were not digested by this enzyme. The o bservation of differing effects of neutrophil gelatinase B on the proteolys is of IL-8 versus other CXC chemokines and on CXC receptor usage by process ed IL-8 yielded insights into the relative activities of chemokines. This l ed to a better understanding of regulator (IL-8) and effector molecules (ge latinase B) of neutrophils and of mechanisms underlying leukocytosis, shock syndromes, and stem cell mobilization by IL-8. (C) 2000 by The American So ciety of Hematology.