Quantum proteolytic activation of chemokine CCL15 by neutrophil granulocytes modulates mononuclear cell adhesiveness.
Monocyte infiltration into inflammatory sites is generally preceded by neutrophils. We show here that neutrophils may support this process by activation of CCL15, a human chemokine circulating in blood plasma. Neutrophils were found to release CCL15 proteolytic activity in the course of hemofiltration of blood from renal insufficiency patients. Processing of CCL15 immunoreactivity (IR) in the pericellular space is suggested by a lack of proteolytic activity in blood and blood filtrate, but a shift of the retention time (t(R)) of CCL15-IR, detected by chromatographic separation of CCL15-IR in blood and hemofiltrate. CCL15 molecules with N-terminal deletions of 23 (delta23) and 26 (delta26) aa were identified as main proteolytic products in hemofiltrate. Neutrophil cathepsin G was identified as the principal protease to produce delta23 and delta26 CCL15. Also, elastase displays CCL15 proteolytic activity and produces a delta21 isoform. Compared with full-length CCL15, delta23 and delta26 isoforms displayed a significantly increased potency to induce calcium fluxes and chemotactic activity on monocytes and to induce adhesiveness of mononuclear cells to fibronectin. Thus, our findings indicate that activation of monocytes by neutrophils is at least in part induced by quantum proteolytic processing of circulating or endothelium-bound CCL15 by neutrophil cathepsin G.
Richter
Rudolf
R
IPF PharmaCeuticals GmbH, Hannover, Germany. Rudorichter@gmx.de
Bistrian
Roxana
R
Escher
Sylvia
S
Forssmann
Wolf-Georg
WG
Vakili
Jalal
J
Henschler
Reinhard
R
Spodsberg
Nikolaj
N
Frimpong-Boateng
Adjoa
A
Forssmann
Ulf
U
D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism; D056649:Cathepsin G; D002403:Cathepsins / Q000097:blood / Q000378:metabolism*; D002448:Cell Adhesion / Q000276:immunology; D019742:Chemokines, CC / Q000097:blood / Q000378:metabolism*; D002634:Chemotaxis, Leukocyte / Q000276:immunology; D002851:Chromatography, High Pressure Liquid; D006224:Cricetinae; D005353:Fibronectins / Q000378:metabolism; D006440:Hemofiltration; D006801:Humans; D006868:Hydrolysis; D007676:Kidney Failure, Chronic / Q000097:blood / Q000276:immunology / Q000628:therapy; D019272:Leukocyte Elastase / Q000097:blood / Q000378:metabolism*; D019402:Macrophage Inflammatory Proteins; D008875:Middle Aged; D009000:Monocytes / Q000166:cytology / Q000276:immunology*; D015846:Monokines / Q000097:blood / Q000378:metabolism*; D018375:Neutrophil Activation / Q000276:immunology*; D010446:Peptide Fragments / Q000097:blood / Q000378:metabolism; D011485:Protein Binding / Q000276:immunology; D020033:Protein Isoforms / Q000097:blood / Q000378:metabolism; D011499:Protein Processing, Post-Translational / Q000276:immunology; D017384:Sequence Deletion; D012697:Serine Endopeptidases / Q000097:blood / Q000378:metabolism*
C108814:CCL15 protein, human; D019742:Chemokines, CC; D005353:Fibronectins; D019402:Macrophage Inflammatory Proteins; D015846:Monokines; D010446:Peptide Fragments; D020033:Protein Isoforms; D002403:Cathepsins; D012697:Serine Endopeptidases; C534094:CTSG protein, human; D056649:Cathepsin G; D019272:Leukocyte Elastase; D002118:Calcium