Proinflammatory mediators elicit secretion of the intracellular B-lymphocyte stimulator pool (BLyS) that is stored in activated neutrophils: implications for inflammatory diseases

Abstract

We have recently shown that granulocytecolony-stimulating factor (G-CSF)-and interferon-␥ (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 (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/GRO␣, CXCL8/IL-8, C5a, immune complexes, tumor necrosis factor-␣ (TNF-␣), leukotriene B 4 , 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. IntroductionB-lymphocyte stimulator (BLyS) is a recently identified member of the tumor necrosis factor (TNF) ligand superfamily that is important in B-cell differentiation, survival, and regulation of immunoglobulin production. 1,2 BLyS exists as a type 2 membrane protein and a soluble protein, 3,4 and its expression seems to be mainly, but not exclusively, restricted to cells of myeloid origin, including activated monocytes, macrophages, myeloid dendritic cells, and neutrophils. 5,6 BLyS is also known as BAFF (B-cell activator factor belonging to the TNF family), THANK (TNF homolog activating apoptosis, NF-B, and JNK), and TALL-1 (TNF-and ApoL-related leukocyte-expressed ligand 1), and it exerts its effect by binding to 3 receptors: transmembrane activator and CAML interactor (TACI), B-cell maturation antigen (BCMA), and BAFF receptor (BAFF-R). 1,2 The requirement of BLyS for humoral immune response has been clearly evidenced in mice lacking BLyS, which exhibit profound deficiencies in peripheral B-cell development and maturation and a strong impairment in T cell-dependent and T cellindependent antibody responses. 1,2 On the other hand, studies reported in the literature suggest a role of soluble BLyS in the pathogenesis of autoimmune diseases. For instance, transgenic mice overexpressing soluble BLyS develop a syndrome that has similarities with systemic lupus erythematosus (SLE) in humans. 1,2 Consistent with these observations, elevated serum BLyS levels have been found in patients with SLE and Sjögren syndrome and in patients with rheumatoid arthritis (RA). 1,2 In addition, elevated BLyS levels have been detected in patients with non-Hodgkin ...

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