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.
Division of Laboratory and Regenerative Medicine, School of Medicine, University of Manchester, Manchester, UK. christine.lemaitre@manchester.ac.uk
Christine Lyn
CL
Le Maitre
Anthony J
AJ
Freemont
Judith Alison
JA
Hoyland
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