Chemokines in Wegener's granulomatosis : clinical and experimental studies

Abstract

BACKGROUND: Wegener’s granulomatosis (WG) is a severe and potentially life-threatening disease characterized by necrotizing granulomatous vasculitis of small- to medium-sized blood vessels. Chemokines are powerful inflammatory mediators, contributing to inflammation through attraction of immune cells, and are, consequently, involved in several inflammatory and autoimmune disorders, such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). It has never been established, however, whether chemokines are also involved in the pathophysiology of WG. METHODS: 1) Serum from 14 WG patients and 9 healthy controls was analyzed with respect to circulating levels of the CC chemokines monocyte chemoattractant protein (MCP)-1, macrophage inflammatory protein (MIP)-1á, and regulated on activation normal T-cell expressed and secreted (RANTES), and the CXC chemokines epithelial cell-derived neutrophil-activating factor (ENA)-78 and interleukin (IL)-8. 2) Peripheral blood mononuclear cells (PBMC) from 9 WG patients and 9 healthy controls were stimulated in vitro with staphylococcal enterotoxin B (SEB) and methylprednisolone (MP), and the resultant levels of chemokine gene expression and secretion were measured by real-time reverse transcriptase – polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assays (ELISA), respectively. RESULTS: 1) The serum levels of MCP-1 and RANTES were significantly elevated in WG patients, compared to healthy controls. Moreover, patients with active disease displayed a trend for lower RANTES levels and higher ENA-78 levels in the systemic circulation than patients in remission. 2) In PBMC from healthy controls all chemokines investigated were down-regulated following treatment in vitro with MP, considering both protein and mRNA levels. On the other hand, MP-mediated suppression of chemokine secretion from PBMC isolated from WG patients was only evident for IL-8, whereas the gene expression of IL-8, ENA-78, and RANTES was also down-regulated. While effective in inhibiting elevated levels of chemokine secretion following stimulation with SEB, MP failed to counteract the SEB-induced up-regulation of gene expression, in both WG patients and healthy controls. CONCLUSION: The elevated circulatory chemokine levels observed in WG patients and the in vitro down-regulation of chemokine levels following treatment with MP in vitro suggest that chemokines may indeed be involved in the pathophysiology of Wegener’s granulomatosis.