Proinflammatory mediators elicit secretion of the intracellular B-lymphocyte stimulator pool (BLyS) that is stored in activated neutrophils: implications for inflammatory diseases.
We have recently shown that granulocyte-colony-stimulating factor (G-CSF)- and interferon-gamma (IFN-gamma)-activated human neutrophils accumulate and release remarkable amounts of soluble B-lymphocyte stimulator (BLyS) in vitro. In this study, we provide evidence that neutrophils migrating into skin window exudates (SWEs) developed in healthy volunteers and in patients with rheumatoid arthritis (RA), synthesized, and released BLyS in response to locally produced G-CSF. Accordingly, the concentrations of soluble BLyS in SWEs were significantly more elevated than in serum. Because the levels of SWE BLyS, but not SWE G-CSF, were higher in patients with RA than in healthy subjects, we examined the effect of CXCL8/IL-8, C5a, and other proinflammatory mediators that dramatically accumulate in RA SWEs and in inflamed synovial fluids. We show that CXCL1/GROalpha, CXCL8/IL-8, C5a, immune complexes, tumor necrosis factor-alpha (TNF-alpha), leukotriene B4, N-formyl-methionyl-leucyl-phenylalanine (fMLP), and lipopolysaccharide (LPS), which by themselves do not induce BLyS de novo synthesis, act as potent secretagogues for BLyS, which is mainly stored in Golgi-related compartments within G-CSF-treated neutrophils, as determined by immunogold electron microscopy. This action is pivotal in greatly amplifying neutrophil-dependent BLyS release in SWEs of patients with RA compared with healthy subjects. Collectively, our data uncover a novel mechanism that might dramatically exacerbate the release of BLyS by neutrophils during pathologic inflammatory responses.
Scapini
Patrizia
P
Department of Pathology, University of Verona, Verona, Italy.
Carletto
Antonio
A
Nardelli
Bernardetta
B
Calzetti
Federica
F
Roschke
Viktor
V
Merigo
Flavia
F
Tamassia
Nicola
N
Pieropan
Sara
S
Biasi
Domenico
D
Sbarbati
Andrea
A
Sozzani
Silvano
S
Bambara
Lisa
L
Cassatella
Marco A
MA
D000328:Adult; D000368:Aged; D001172:Arthritis, Rheumatoid / Q000276:immunology* / Q000378:metabolism*; D053264:B-Cell Activating Factor; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D008875:Middle Aged; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D012867:Skin / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism* / Q000494:pharmacology
D053264:B-Cell Activating Factor; D018836:Inflammation Mediators; D008565:Membrane Proteins; C505719:TNFSF13B protein, human; D014409:Tumor Necrosis Factor-alpha; D009240:N-Formylmethionine Leucyl-Phenylalanine