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.
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-1beta (IL-1beta), IL-6, IL-10, tumor necrosis factor alpha (TNF-alpha), transforming growth factor beta (TGFbeta), 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.
Kossakowska
A E
AE
Department of Pathology, University of Calgary, Calgary Laboratory Services, Calgary, Alberta, Canada. anna.kossakowska@crha-health.ab.ca
Edwards
D R
DR
Prusinkiewicz
C
C
Zhang
M C
MC
Guo
D
D
Urbanski
S J
SJ
Grogan
T
T
Marquez
L A
LA
Janowska-Wieczorek
A
A
D017364:Collagenases / Q000235:genetics*; D017077:Culture Media, Conditioned; D016207:Cytokines / Q000235:genetics*; D017931:DNA Primers; D018093:Gelatinases / Q000235:genetics*; D015971:Gene Expression Regulation, Enzymologic / Q000276:immunology / Q000502:physiology; D015972:Gene Expression Regulation, Neoplastic / Q000276:immunology / Q000502:physiology*; D006133:Growth Substances / Q000235:genetics*; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics*; D008228:Lymphoma, Non-Hodgkin / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D008666:Metalloendopeptidases / Q000235:genetics*; D009361:Neoplasm Invasiveness; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics*; D014407:Tumor Cells, Cultured
D017077:Culture Media, Conditioned; D016207:Cytokines; D017931:DNA Primers; D006133:Growth Substances; D015850:Interleukin-6; D019715:Tissue Inhibitor of Metalloproteinase-1; D017364:Collagenases; D018093:Gelatinases; D008666:Metalloendopeptidases; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9