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Blood, 15 January 2005, Vol. 105, No. 2, pp. 830-837.
Prepublished online as a Blood First Edition Paper on September 9, 2004; DOI 10.1182/blood-2004-02-0564.
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Submitted February 13, 2004
Accepted August 31, 2004
Proinflammatory mediators elicit the secretion of the intracellular B-lymphocyte stimulator (BLyS) pool that is stored in activated neutrophils: implications for inflammatory diseases
Patrizia Scapini, Antonio Carletto, Bernardetta Nardelli, Federica Calzetti, Viktor Roschke, Flavia Merigo, Nicola Tamassia, Sara Pieropan, Domenico Biasi, Andrea Sbarbati, Silvano Sozzani, Lisa Bambara, and Marco A Cassatella*
Department of Pathology, Division of General Pathology, University of Verona, Verona, Italy
Department of Clinical and Experimental Medicine, Division of Rheumatology, University of Verona, Verona, Italy
Human Genome Sciences, Inc., Rockville, MD, USA
Department of Morphological and Biomedical Sciences, Division of Anatomy and Histology, University of Verona, Verona, Italy
Department of Biotechnology, Division of General Pathology and Immunology, University of Brescia, Milano, Italy
* Corresponding author; email: marco.cassatella{at}univr.it.
We have recently shown that G-CSF- and IFN -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 (SWE), developed in both healthy volunteers and rheumatoid arthritis (RA) patients, synthesize and release BLyS in response to locally produced G-CSF. Accordingly, the concentrations of soluble BLyS in SWE were significantly more elevated than in serum. Because the levels of SWE BLyS, but not SWE G-CSF, were higher in RA patients than in healthy subjects, we examined the effect of CXCL8/IL-8, C5a and other proinflammatory mediators that dramatically accumulate in RA SWE and/or inflamed synovial fluids. We show that CXCL1/GRO , CXCL8/IL-8, C5a, immune complexes, TNF , leukotriene-B4, fMLP and 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 SWE of RA patients relative to healthy donors. Collectively, our data uncover a novel mechanism that might dramatically exacerbate the release of BLyS by neutrophils during pathological inflammatory responses.

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