Degradation of interleukin 1beta by matrix metalloproteinases.
Matrix metalloproteinases (MMPs) and interleukin 1 (IL-1) are implicated in inflammation and tissue destruction, where IL-1 is a potent stimulator of connective tissue cells to produce the extracellular matrix-degrading MMPs. Here, we report that IL-1beta, but not IL-1alpha, is degraded by MMP-1 (interstitial collagenase), MMP-2 (gelatinase A), MMP-3 (stromelysin 1), and MMP-9 (gelatinase B). This degradation was effectively blocked by tissue inhibitor of metalloproteinases (TIMP)-1. When IL-1beta was treated with MMPs it lost the ability to enhance the synthesis of prostaglandin E2 and pro-MMP-3 in human fibroblasts. The primary cleavage site of IL-1beta by MMP-2 was identified at the Glu25-Leu26 bond. These results suggest that IL-1beta stimulates connective tissue cells to produce MMPs, but activated MMPs in turn negatively regulate the activity of IL-1beta.
Ito
A
A
Department of Biochemistry, Tokyo College of Pharmacy, Horinouchi, Hachioji, Tokyo 192-03, Japan.
Mukaiyama
A
A
Itoh
Y
Y
Nagase
H
H
Thogersen
I B
IB
Enghild
J J
JJ
Sasaguri
Y
Y
Mori
Y
Y
D000595:Amino Acid Sequence; D002460:Cell Line; D017364:Collagenases / Q000378:metabolism*; D015232:Dinoprostone / Q000096:biosynthesis; D004789:Enzyme Activation; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D005354:Fibrosarcoma; D018093:Gelatinases / Q000378:metabolism*; D006023:Glycoproteins / Q000494:pharmacology; D006801:Humans; D007249:Inflammation; D007375:Interleukin-1 / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D007700:Kinetics; D020781:Matrix Metalloproteinase 1; D020778:Matrix Metalloproteinase 2; D019278:Matrix Metalloproteinase 3; D020780:Matrix Metalloproteinase 9; D008666:Metalloendopeptidases / Q000378:metabolism*; D008969:Molecular Sequence Data; D010662:Phenylmercuric Acetate / Q000031:analogs & derivatives / Q000494:pharmacology; D013379:Substrate Specificity; D013439:Sulfhydryl Reagents / Q000494:pharmacology; D019714:Tissue Inhibitor of Metalloproteinases
D006023:Glycoproteins; D007375:Interleukin-1; D013439:Sulfhydryl Reagents; D019714:Tissue Inhibitor of Metalloproteinases; C010024:4-aminophenylmercuriacetate; D017364:Collagenases; D018093:Gelatinases; D008666:Metalloendopeptidases; D019278:Matrix Metalloproteinase 3; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D020781:Matrix Metalloproteinase 1; D015232:Dinoprostone; D010662:Phenylmercuric Acetate