The role of interleukin-1 in the pathogenesis of human intervertebral disc degeneration.
In this study, we investigated the hypotheses that in human intervertebral disc (IVD) degeneration there is local production of the cytokine IL-1, and that this locally produced cytokine can induce the cellular and matrix changes of IVD degeneration. Immunohistochemistry was used to localize five members of the IL-1 family (IL-1alpha, IL-1beta, IL-1Ra (IL-1 receptor antagonist), IL-1RI (IL-1 receptor, type I), and ICE (IL-1beta-converting enzyme)) in non-degenerate and degenerate human IVDs. In addition, cells derived from non-degenerate and degenerate human IVDs were challenged with IL-1 agonists and the response was investigated using real-time PCR for a number of matrix-degrading enzymes, matrix proteins, and members of the IL-1 family. This study has shown that native disc cells from non-degenerate and degenerate discs produced the IL-1 agonists, antagonist, the active receptor, and IL-1beta-converting enzyme. In addition, immunopositivity for these proteins, with the exception of IL-1Ra, increased with severity of degeneration. We have also shown that IL-1 treatment of human IVD cells resulted in increased gene expression for the matrix-degrading enzymes (MMP 3 (matrix metalloproteinase 3), MMP 13 (matrix metalloproteinase 13), and ADAMTS-4 (a disintegrin and metalloproteinase with thrombospondin motifs)) and a decrease in the gene expression for matrix genes (aggrecan, collagen II, collagen I, and SOX6). In conclusion we have shown that IL-1 is produced in the degenerate IVD. It is synthesized by native disc cells, and treatment of human disc cells with IL-1 induces an imbalance between catabolic and anabolic events, responses that represent the changes seen during disc degeneration. Therefore, inhibiting IL-1 could be an important therapeutic target for preventing and reversing disc degeneration.
Le Maitre
Christine Lyn
CL
Division of Laboratory and Regenerative Medicine, School of Medicine, University of Manchester, Manchester, UK. christine.lemaitre@manchester.ac.uk
Freemont
Anthony J
AJ
Hoyland
Judith Alison
JA
D000328:Adult; D000368:Aged; D000704:Analysis of Variance; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology / Q000502:physiology*; D007403:Intervertebral Disc / Q000187:drug effects / Q000473:pathology; D007405:Intervertebral Disc Displacement / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D008159:Lumbar Vertebrae / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D018709:Statistics, Nonparametric
D007375:Interleukin-1