Interleukin-6 Regulation of Matrix Metalloproteinase (MMP-2 and MMP-9) and Tissue Inhibitor of Metalloproteinase (TIMP-1) Expression in Malignant Non-Hodgkin’s Lymphomas

Abstract

We showed previously that human malignant non-Hodgkin’s lymphomas (NHL) degrade extracellular matrix (ECM) components through the action of metalloproteinases and that elevated expression of matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinase-1 (TIMP-1) correlated with a poor clinical outcome in patients with NHL. In the present study we sought to investigate whether there is any correlation between the expression of gelatinases (MMP-2 and MMP-9), TIMP-1, and the expression of cytokines and growth factors such as interleukin-1β (IL-1β), IL-6, IL-10, tumor necrosis factor  (TNF-), transforming growth factor β (TGFβ), and basic fibroblast growth factor (bFGF) in human NHL. In lymphoma tissues obtained from 32 patients, elevated expression of IL-6 correlated significantly with elevated messenger RNA (mRNA) levels of MMP-9, MMP-2, and TIMP-1. Moreover, in human lymphoid cell lines of B- and T-cell origin (Raji, Jurkat, and NC-37), IL-6 stimulated production of MMP-9 and MMP-2 but not TIMP-1. In the Matrigel invasion assay IL-6 significantly upregulated transmigration of Raji and Jurkat cells, which in turn was inhibited by recombinant human TIMP-1 and anti-MMP-9 and MMP-2 antibodies. We postulate that IL-6 may play a role in the clinical aggressiveness of human NHL by stimulating MMP production.

IL‐6 Regulates Extracellular Matrix Remodeling Associated With Aortic Dilation in a Fibrillin‐1 Hypomorphic mgR/mgR Mouse Model of Severe Marfan Syndrome

“…Since macrophages localized mostly to the adventitia, MMP-9 is likely being produced by VSMCs in the media and by macrophages in the adventitia. Similar observations have been made in a bone resorption study 42 and in cancer 43 where IL-6 signaling was found to regulate mRNA expression and biological activities of MMP-2 and -9 through the soluble IL-6 receptor. It remains unclear why IL-6 deficiency did not affect MMP-2 activity in DKO aortas.…”

Interleukin-6 (IL-6) modulates migration and matrix metalloproteinase function in dermal fibroblasts from IL-6KO mice

“…43 Clinically, circulating IL-6 levels are correlated with MMP-9 levels in children recovering from surgery 21 and also with increased MMP-2 and -9 expression in non-Hodgkin lymphoma. 22 In culture, IL-6 has varying effects depending on cell type. IL-6 had little effect on the expression of MMPs in synovial fibroblasts, 25 alveolar macrophages 26 and cardiac fibroblasts.…”

“…19,20 However, the role of IL-6 in the expression of these mediators is often conflicting. Circulating levels of the cytokine correlate with MMP levels, 21,22 yet IL-6 has been shown to either induce 23,24 MMP expression or have no effect [25][26][27][28] in various cell types. The role of IL-6 in TIMP expression is similarly unclear.…”

Matrix metalloproteinase and tissue inhibitors of metalloproteinase secretion by haematopoietic and stromal precursors and their production in normal and leukaemic long‐term marrow cultures

“…Analysis of TIMPs by reverse zymography. LTMC supernatants and media conditioned by adherent and nonadherent cells, BFU-E-, CFU-Meg-or CFU-GM-derived cells and fibroblastic cells were analysed by reverse zymography as previously described (Oliver et al, 1997;Janowska-Wieczorek et al, 1999a;Kossakowska et al, 1999). The samples were electrophoresed in 0´1% SDS (Sigma) and 12% polyacrylamide gels containing 1´75 mg/ml gelatin (Sigma) and 160 ng/ml of proMMP-2 (Cedarlane, Hornby, ON, Canada).…”