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TL1A/DR3 axis involvement in the inflammatory cytokine network during pulmonary sarcoidosis.

Facco M, Cabrelle A, Calabrese F, Teramo A, Cinetto F, Carraro S, Martini V, Calzetti F, Tamassia N, Cassatella MA, Semenzato G, Agostini C - Clin Mol Allergy (2015)

Bottom Line: TNF-like ligand 1A (TL1A), a recently recognized member of the TNF superfamily, and its death domain receptor 3 (DR3), firstly identified for their relevant role in T lymphocyte homeostasis, are now well-known mediators of several immune-inflammatory diseases, ranging from rheumatoid arthritis to inflammatory bowel diseases to psoriasis, whereas no data are available on their involvement in sarcoidosis, a multisystemic granulomatous disease where a deregulated T helper (Th)1/Th17 response takes place.Our results demonstrated a significant higher expression, both at protein and mRNA levels, of TL1A and DR3 in pulmonary T cells and alveolar macrophages of patients with active sarcoidosis as compared to patients with the inactive form of the disease and to controls.Additionally, zymography assays showed that TL1A is able to increase the production of matrix metalloproteinase 9 by sarcoid alveolar macrophages characterized, in patients with the active form of the disease, by reduced mRNA levels of the tissue inhibitor of metalloproteinase (TIMP)-1.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Hematology and Clinical Immunology Branch, Padua University School of Medicine, Padua, Italy ; Venetian Institute of Molecular Medicine, Padua, Italy.

ABSTRACT

Background: TNF-like ligand 1A (TL1A), a recently recognized member of the TNF superfamily, and its death domain receptor 3 (DR3), firstly identified for their relevant role in T lymphocyte homeostasis, are now well-known mediators of several immune-inflammatory diseases, ranging from rheumatoid arthritis to inflammatory bowel diseases to psoriasis, whereas no data are available on their involvement in sarcoidosis, a multisystemic granulomatous disease where a deregulated T helper (Th)1/Th17 response takes place.

Methods: In this study, by flow cytometry, real-time PCR, confocal microscopy and immunohistochemistry analyses, TL1A and DR3 were investigated in the pulmonary cells and the peripheral blood of 43 patients affected by sarcoidosis in different phases of the disease (29 patients with active sarcoidosis, 14 with the inactive form) and in 8 control subjects.

Results: Our results demonstrated a significant higher expression, both at protein and mRNA levels, of TL1A and DR3 in pulmonary T cells and alveolar macrophages of patients with active sarcoidosis as compared to patients with the inactive form of the disease and to controls. In patients with sarcoidosis TL1A was strongly more expressed in the lung than the blood, i.e., at the site of the involved organ. Additionally, zymography assays showed that TL1A is able to increase the production of matrix metalloproteinase 9 by sarcoid alveolar macrophages characterized, in patients with the active form of the disease, by reduced mRNA levels of the tissue inhibitor of metalloproteinase (TIMP)-1.

Conclusions: These data suggest that TL1A/DR3 interactions are part of the extended and complex immune-inflammatory network that characterizes sarcoidosis during its active phase and may contribute to the pathogenesis and to the progression of the disease.

No MeSH data available.


Related in: MedlinePlus

Immunohistochemistry for TL1A and DR3 expression in representative patients with active (A, B) and refractory sarcoidosis and pulmonary fibrosis (C, D). A, B. TL1A and DR3 are expressed at high intensity by macrophagic, both epitheliod and multinucleated, cells and lymphocytes infiltrating the lung biopsy of the patient with active sarcoidosis. The black arrows indicate positive metaplastic epithelial cells. C, D. In the lung specimen obtained from a patient with refractory sarcoidosis and pulmonary fibrosis, pulmonary cells were mainly non reactive for TL1A and DR3; a weak immunostaining was only seen in some epitheliod cells (arrows). Note marked fibrosis around the granulomatous nodule. Original magnification 400x
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Fig3: Immunohistochemistry for TL1A and DR3 expression in representative patients with active (A, B) and refractory sarcoidosis and pulmonary fibrosis (C, D). A, B. TL1A and DR3 are expressed at high intensity by macrophagic, both epitheliod and multinucleated, cells and lymphocytes infiltrating the lung biopsy of the patient with active sarcoidosis. The black arrows indicate positive metaplastic epithelial cells. C, D. In the lung specimen obtained from a patient with refractory sarcoidosis and pulmonary fibrosis, pulmonary cells were mainly non reactive for TL1A and DR3; a weak immunostaining was only seen in some epitheliod cells (arrows). Note marked fibrosis around the granulomatous nodule. Original magnification 400x

Mentions: Immunohistochemical analysis confirmed the expression of TL1A and its receptor DR3 by sarcoid pulmonary T cells infiltrating surgical pulmonary biopsies obtained from two patients with active sarcoidosis (Fig. 3a and b). When the cell sources of TL1A in sarcoid tissue was investigated, we showed that the cytokine was preferentially expressed by macrophage multinucleated giant cells and T cells in the granuloma, even if endothelial and metaplastic epithelial cells bore the two molecules. Immunohistochemical analysis of biopsies from one patient with refractory sarcoidosis and pulmonary fibrosis showed that lung T cells were mainly nonreactive for TL1A and DR3, whereas some epitheliod cells were weakly positive (Fig. 3c and d).Fig. 3


TL1A/DR3 axis involvement in the inflammatory cytokine network during pulmonary sarcoidosis.

Facco M, Cabrelle A, Calabrese F, Teramo A, Cinetto F, Carraro S, Martini V, Calzetti F, Tamassia N, Cassatella MA, Semenzato G, Agostini C - Clin Mol Allergy (2015)

Immunohistochemistry for TL1A and DR3 expression in representative patients with active (A, B) and refractory sarcoidosis and pulmonary fibrosis (C, D). A, B. TL1A and DR3 are expressed at high intensity by macrophagic, both epitheliod and multinucleated, cells and lymphocytes infiltrating the lung biopsy of the patient with active sarcoidosis. The black arrows indicate positive metaplastic epithelial cells. C, D. In the lung specimen obtained from a patient with refractory sarcoidosis and pulmonary fibrosis, pulmonary cells were mainly non reactive for TL1A and DR3; a weak immunostaining was only seen in some epitheliod cells (arrows). Note marked fibrosis around the granulomatous nodule. Original magnification 400x
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4522997&req=5

Fig3: Immunohistochemistry for TL1A and DR3 expression in representative patients with active (A, B) and refractory sarcoidosis and pulmonary fibrosis (C, D). A, B. TL1A and DR3 are expressed at high intensity by macrophagic, both epitheliod and multinucleated, cells and lymphocytes infiltrating the lung biopsy of the patient with active sarcoidosis. The black arrows indicate positive metaplastic epithelial cells. C, D. In the lung specimen obtained from a patient with refractory sarcoidosis and pulmonary fibrosis, pulmonary cells were mainly non reactive for TL1A and DR3; a weak immunostaining was only seen in some epitheliod cells (arrows). Note marked fibrosis around the granulomatous nodule. Original magnification 400x
Mentions: Immunohistochemical analysis confirmed the expression of TL1A and its receptor DR3 by sarcoid pulmonary T cells infiltrating surgical pulmonary biopsies obtained from two patients with active sarcoidosis (Fig. 3a and b). When the cell sources of TL1A in sarcoid tissue was investigated, we showed that the cytokine was preferentially expressed by macrophage multinucleated giant cells and T cells in the granuloma, even if endothelial and metaplastic epithelial cells bore the two molecules. Immunohistochemical analysis of biopsies from one patient with refractory sarcoidosis and pulmonary fibrosis showed that lung T cells were mainly nonreactive for TL1A and DR3, whereas some epitheliod cells were weakly positive (Fig. 3c and d).Fig. 3

Bottom Line: TNF-like ligand 1A (TL1A), a recently recognized member of the TNF superfamily, and its death domain receptor 3 (DR3), firstly identified for their relevant role in T lymphocyte homeostasis, are now well-known mediators of several immune-inflammatory diseases, ranging from rheumatoid arthritis to inflammatory bowel diseases to psoriasis, whereas no data are available on their involvement in sarcoidosis, a multisystemic granulomatous disease where a deregulated T helper (Th)1/Th17 response takes place.Our results demonstrated a significant higher expression, both at protein and mRNA levels, of TL1A and DR3 in pulmonary T cells and alveolar macrophages of patients with active sarcoidosis as compared to patients with the inactive form of the disease and to controls.Additionally, zymography assays showed that TL1A is able to increase the production of matrix metalloproteinase 9 by sarcoid alveolar macrophages characterized, in patients with the active form of the disease, by reduced mRNA levels of the tissue inhibitor of metalloproteinase (TIMP)-1.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Hematology and Clinical Immunology Branch, Padua University School of Medicine, Padua, Italy ; Venetian Institute of Molecular Medicine, Padua, Italy.

ABSTRACT

Background: TNF-like ligand 1A (TL1A), a recently recognized member of the TNF superfamily, and its death domain receptor 3 (DR3), firstly identified for their relevant role in T lymphocyte homeostasis, are now well-known mediators of several immune-inflammatory diseases, ranging from rheumatoid arthritis to inflammatory bowel diseases to psoriasis, whereas no data are available on their involvement in sarcoidosis, a multisystemic granulomatous disease where a deregulated T helper (Th)1/Th17 response takes place.

Methods: In this study, by flow cytometry, real-time PCR, confocal microscopy and immunohistochemistry analyses, TL1A and DR3 were investigated in the pulmonary cells and the peripheral blood of 43 patients affected by sarcoidosis in different phases of the disease (29 patients with active sarcoidosis, 14 with the inactive form) and in 8 control subjects.

Results: Our results demonstrated a significant higher expression, both at protein and mRNA levels, of TL1A and DR3 in pulmonary T cells and alveolar macrophages of patients with active sarcoidosis as compared to patients with the inactive form of the disease and to controls. In patients with sarcoidosis TL1A was strongly more expressed in the lung than the blood, i.e., at the site of the involved organ. Additionally, zymography assays showed that TL1A is able to increase the production of matrix metalloproteinase 9 by sarcoid alveolar macrophages characterized, in patients with the active form of the disease, by reduced mRNA levels of the tissue inhibitor of metalloproteinase (TIMP)-1.

Conclusions: These data suggest that TL1A/DR3 interactions are part of the extended and complex immune-inflammatory network that characterizes sarcoidosis during its active phase and may contribute to the pathogenesis and to the progression of the disease.

No MeSH data available.


Related in: MedlinePlus