Human T cells stimulate fibroblast-mediated degradation of extracellular matrix in vitro.
Several chronic diseases are characterized by inflammation, T cell recruitment and tissue remodelling. We hypothesized that activated T cells may stimulate remodelling of extracellular matrix (ECM) in vitro. Total T cells (CD3+) as well as CD4+ and CD8+ subsets were isolated from peripheral blood and stimulated, after which conditioned media (CM) were obtained. CM was added to human lung fibroblasts in three-dimensional collagen gels and the area of gels was measured daily. Hydroxyproline was determined as a measure of collagen degradation in the gels. Matrix metalloproteinase (MMP) activity in the culture media was analysed by gelatine zymography. Cytokine secretion of stimulated CD4+ and CD8+ T cells was analysed. CD3+ CM augmented collagen gel contraction in a time- and dose-dependent manner (P < 0.0001). CD4+ T cell CM was more potent than CD8+ T cell CM (P < 0.001). CD3+ CM and CD4+ T cell CM, but not CD8+ T cell CM, stimulated fibroblast-mediated collagen degradation and MMP-9 activity. A broad-spectrum MMP-inhibitor added to the culture system inhibited both gel contraction and MMP activity. Activated CD4+ T cells secreted significantly more tumour necrosis factor (TNF) and interleukin (IL)-6 compared to CD8+ T cells. CD3+ CM from patients with chronic obstructive pulmonary disease stimulated fibroblast-mediated collagen gel contraction to the same magnitude as CD3+ CM from healthy controls. In conclusion, activated CD4+ T cells can stimulate fibroblast-mediated degradation of ECM in vitro. This could be a mechanism by which activated T cells stimulate degradation of lung tissue leading to pulmonary emphysema.
Mikko
M
M
Karolinska Institutet, Department of Medicine, Unit of Respiratory Medicine, Karolinska University Hospital Solna, Stockholm, Sweden. mikael.mikko@ki.se
Fredriksson
K
K
Wahlström
J
J
Eriksson
P
P
Grunewald
J
J
Sköld
C M
CM
D000328:Adult; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002450:Cell Communication; D049109:Cell Proliferation; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D017077:Culture Media, Conditioned; D016207:Cytokines / Q000378:metabolism; D004151:Dipeptides / Q000494:pharmacology; D005109:Extracellular Matrix / Q000378:metabolism*; D005260:Female; D005347:Fibroblasts / Q000502:physiology*; D005786:Gene Expression Regulation / Q000276:immunology; D006801:Humans; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D008875:Middle Aged; D011480:Protease Inhibitors / Q000494:pharmacology; D029424:Pulmonary Disease, Chronic Obstructive / Q000097:blood; D012333:RNA, Messenger / Q000235:genetics; D013601:T-Lymphocytes / Q000502:physiology*
D017077:Culture Media, Conditioned; D016207:Cytokines; D004151:Dipeptides; D061965:Matrix Metalloproteinase Inhibitors; C078131:N-(2(R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl)-L-tryptophan methylamide; D011480:Protease Inhibitors; D012333:RNA, Messenger; D003094:Collagen; D020780:Matrix Metalloproteinase 9