The Role of Interleukin-1 in the Pathogenesis of Human
The Role of Interleukin-1 in the Pathogenesis of Human
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-1α, IL-1β, IL-1Ra (IL-1 receptor antagonist), IL-1RI (IL-1 receptor, type I), and ICE (IL-1β-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-1β-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.
Low back pain is a common, debilitating, and economically important disorder. Current evidence implicates loss of intervertebral disc (IVD) matrix consequent upon disc 'degeneration' as a major cause of low back pain. Although many treatments aimed at relieving back pain are directed towards the degenerate IVDs (e.g. removal of protruding disc material, disc replacement, etc.), none of these are aimed at the processes of degeneration. Modern advances in therapeutics, particularly cell and tissue engineering, offer potential methods for inhibiting or reversing IVD degeneration that have not previously been possible, but they require a level of understanding of the pathobiology of degeneration of the IVDs that is not currently available.
Degeneration is characterized by increased degradation of the normal IVD matrix by locally produced matrix metalloproteinases (MMPs) and ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs). In addition, the nature of the matrix produced in the degenerate IVDs differs from that in normal IVDs, as a consequence of switches in the production of collagen within the inner annulus fibrosus (IAF), and nucleus pulposus (NP) from type II to type I and in the synthesis of proteoglycan from aggrecan to versican, biglycan, and decorin. The resultant changes within the extracellular matrix have a number of consequences, resulting in loss of structural integrity, decreased hydration, and a reduced ability to withstand load.
Similar matrix changes have been reported in articular cartilage in osteoarthritis. In this disease, the body of evidence points towards these being part of a more profound change in chondrocyte biosynthesis driven by local production of IL-1 and tumour necrosis factor α. Despite the similarities between IVD degeneration and the cartilage changes in osteoarthritis, there has been relatively little interest in exploring the possibility that the disease processes involved in IVD degeneration might be driven by similar alterations in local tissue cytokine biology, and particularly by IL-1 and tumour necrosis factor α. TNF α has been implicated in disc herniation and sciatic pain, but not in disc degeneration. There is, however, some circumstantial evidence implicating IL-1 in human IVD degeneration. This evidence comes from studies on annulus fibrosus (AF) cells from rabbit IVDs and NP cells from ovine and rabbit IVDs, which suggest that IL-1 may have similar effects on the chondrocyte-like cells of IVDs to those seen in articular chondrocytes. IL-1 has been identified in herniated, displaced human discal tissue but has not been investigated within the degenerate IVDs themselves. Two recent genetic studies suggest that IL-1 gene cluster polymorphisms contribute to the pathogenesis of lumbar IVD degeneration and low back pain. Despite these data, there is no clear evidence that IL-1 is synthesized by native human disc cells (as opposed to cells within herniated disc tissue) or whether it can induce the altered synthesis of matrix molecules and degrading enzyme production by human IVD cells characteristic of IVD degeneration, particularly in the NP, where degenerative changes first appear.
This study investigates two hypotheses: that in human IVD degeneration, there is local production of the cytokine IL-1 by native disc cells, and that locally produced IL-1 can induce the cellular and matrix changes of IVD 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-1α, IL-1β, IL-1Ra (IL-1 receptor antagonist), IL-1RI (IL-1 receptor, type I), and ICE (IL-1β-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-1β-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.
Low back pain is a common, debilitating, and economically important disorder. Current evidence implicates loss of intervertebral disc (IVD) matrix consequent upon disc 'degeneration' as a major cause of low back pain. Although many treatments aimed at relieving back pain are directed towards the degenerate IVDs (e.g. removal of protruding disc material, disc replacement, etc.), none of these are aimed at the processes of degeneration. Modern advances in therapeutics, particularly cell and tissue engineering, offer potential methods for inhibiting or reversing IVD degeneration that have not previously been possible, but they require a level of understanding of the pathobiology of degeneration of the IVDs that is not currently available.
Degeneration is characterized by increased degradation of the normal IVD matrix by locally produced matrix metalloproteinases (MMPs) and ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs). In addition, the nature of the matrix produced in the degenerate IVDs differs from that in normal IVDs, as a consequence of switches in the production of collagen within the inner annulus fibrosus (IAF), and nucleus pulposus (NP) from type II to type I and in the synthesis of proteoglycan from aggrecan to versican, biglycan, and decorin. The resultant changes within the extracellular matrix have a number of consequences, resulting in loss of structural integrity, decreased hydration, and a reduced ability to withstand load.
Similar matrix changes have been reported in articular cartilage in osteoarthritis. In this disease, the body of evidence points towards these being part of a more profound change in chondrocyte biosynthesis driven by local production of IL-1 and tumour necrosis factor α. Despite the similarities between IVD degeneration and the cartilage changes in osteoarthritis, there has been relatively little interest in exploring the possibility that the disease processes involved in IVD degeneration might be driven by similar alterations in local tissue cytokine biology, and particularly by IL-1 and tumour necrosis factor α. TNF α has been implicated in disc herniation and sciatic pain, but not in disc degeneration. There is, however, some circumstantial evidence implicating IL-1 in human IVD degeneration. This evidence comes from studies on annulus fibrosus (AF) cells from rabbit IVDs and NP cells from ovine and rabbit IVDs, which suggest that IL-1 may have similar effects on the chondrocyte-like cells of IVDs to those seen in articular chondrocytes. IL-1 has been identified in herniated, displaced human discal tissue but has not been investigated within the degenerate IVDs themselves. Two recent genetic studies suggest that IL-1 gene cluster polymorphisms contribute to the pathogenesis of lumbar IVD degeneration and low back pain. Despite these data, there is no clear evidence that IL-1 is synthesized by native human disc cells (as opposed to cells within herniated disc tissue) or whether it can induce the altered synthesis of matrix molecules and degrading enzyme production by human IVD cells characteristic of IVD degeneration, particularly in the NP, where degenerative changes first appear.
This study investigates two hypotheses: that in human IVD degeneration, there is local production of the cytokine IL-1 by native disc cells, and that locally produced IL-1 can induce the cellular and matrix changes of IVD degeneration.
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