Transforming growth factor-beta1 in sarcoidosis

Abstract

Transforming growth factor-beta (TGF-beta) is a cytokine that promotes extracellular matrix accumulation and inhibits matrix degradation. Although the natural course of sarcoidosis is usually favourable, granuloma healing in the lung may result in pulmonary fibrosis and respiratory impairment in some patients. In this study TGF-beta1 was evaluated in bronchoalveolar lavage (BAL) fluid and culture supernatants of alveolar macrophages (AM) from 73 patients with biopsy-proven sarcoidosis. Disease activity was defined when patients recently developed or increased symptoms (cough, dyspnoea, systemic symptoms) and/or demonstrated increasing opacities on chest radiography. Pulmonary function tests were performed in all patients including forced expiratory volume in one second (FEV1), forced vital capacity (FVC), total lung capacity (TLC) and the diffusing capacity of the lung for carbon monoxide (DL,CO). Fourteen patients with idiopathic pulmonary fibrosis (IPF) and 14 healthy subjects were investigated as a control group. Immunohistochemistry was used to evaluate the cell distribution of TGF-beta1 on lung specimens. TGF-beta1 levels in BAL and in AM supernatants were not different between sarcoidosis and healthy subjects, whereas they were markedly increased in IPF. However, the TGF-beta1 level was significantly increased in BAL fluid but not in AM supernatants from sarcoidosis with altered lung function, compared with patients with normal lung function. The TGF-beta1 level in BAL was increased in active sarcoidosis but this increased level was mainly related to the higher level observed in patients with altered lung function. TGF-beta1 levels in BAL correlated significantly with the lymphocyte percentage. TGF-beta1 staining assessed by immunohistochemistry was intense in epithelioid histiocytes comprising non-necrotizing granuloma and in bronchiolar epithelial cells, in hyperplastic type II pneumocytes and occasionally in AM. This study supports the hypothesis that overproduction of transforming growth factor-beta1 is associated with functional impairment in patients with pulmonary sarcoidosis.

Increased interleukin-13 expression in patients with sarcoidosis

“…Increased levels of TGFβ have been reported in the BAL fluid of patients with sarcoidosis, 13 but a recent study also reported increased TGFβ levels in the BAL fluid of patients with altered lung function. 14 The role of TGFβ therefore still needs to be defined. Enhanced secretion of IL-10 has been observed from alveolar macrophages but not from BAL fluid cells of patients with sarcoidosis.…”

Deficient and Dysfunctional Regulatory T Cells in the Lungs of Chronic Beryllium Disease Subjects

“…TGF-b1 is a pleiotropic cytokine with effects on cell growth and differentiation, extracellular matrix formation and fibrosis, and immunomodulation. For example, elevated levels of active TGF-b1 were seen in the BAL of fibrotic sarcoidosis patients compared with normal control subjects (48). Several functional single nucleotide polymorphisms within the TGF-b1 gene have been identified, including C2509T, codon 10 (T 1 29C), and codon 25 (G 1 74C) (49).…”

Genetics of Sarcoidosis

“…[86,87] The variant allele C of -509T/C and C of codon 10 are associated with higher TGF-β1 protein levels in the serum and the codon 10 variant is associated with increased mRNA levels in PBMC. [88,89] TGF-β1 levels in the BAL and alveolar macrophage supernatant are higher in patients with active sarcoidosis and especially in those with pulmonary function changes, [90] there was also a positive correlation with BAL lymphocytosis. [90] No association was found between sarcoidosis and 2 polymorphisms (codon 10, T869C) in the TGF-β1 gene in a Japanese sarcoidosis cohort and no relationship with Scadding chest x-ray stage was found either.…”

“…[88,89] TGF-β1 levels in the BAL and alveolar macrophage supernatant are higher in patients with active sarcoidosis and especially in those with pulmonary function changes, [90] there was also a positive correlation with BAL lymphocytosis. [90] No association was found between sarcoidosis and 2 polymorphisms (codon 10, T869C) in the TGF-β1 gene in a Japanese sarcoidosis cohort and no relationship with Scadding chest x-ray stage was found either. [91] Codon 10 was also not associated with sarcoidosis in a German cohort [92].…”