IL-17, IL-1β and TNF-α stimulate VEGF production by dedifferentiated chondrocytes

Honorati, Maria Cristina; Cattini, Luca; Facchini, Andrea

doi:10.1016/j.joca.2004.05.009

Cited by 80 publications

(71 citation statements)

References 38 publications

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“…Further, chondrocyte phenotype modulations in OA in the form of dedifferentiation (58,59), proliferation (60), apoptosis (61), and hypertrophy (46,62) have been proposed. We found that many genes (e.g., Ltbp2, Phex, and Reln) were regulated similarly in both degrading cartilage and differentiating chondrocytes, positioning mechanisms leading to hypertrophic differentiation of chondrocytes in early OA.…”

Section: Discussionmentioning

confidence: 99%

Global analyses of gene expression in early experimental osteoarthritis

Appleton¹,

Pitelka²,

Henry³

et al. 2007

Arthritis & Rheumatism

222

224

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Objective. To analyze genome-wide changes in chondrocyte gene expression in a surgically induced model of early osteoarthritis (OA) in rats, to assess the similarity of this model to human OA, and to identify genes and mechanisms leading to OA pathogenesis.Methods. OA was surgically induced in 5 rats by anterior cruciate ligament transection and partial medial meniscectomy. Sham surgery was performed in 5 additional animals, which were used as controls. Both groups underwent 4 weeks of forced mobilization, 3 times per week. RNA was extracted directly from articular chondrocytes in the OA (operated), contralateral, and sham-operated knees. Affymetrix GeneChip expression arrays were used to assess genome-wide changes in gene expression. Expression patterns of selected dysregulated genes, including Col2a1, Mmp13, Adamts5, Ctsc, Ptges, and Cxcr4, were validated by real-time polymerase chain reaction, immunofluorescence, or immunohistochemistry 2, 4, and 8 weeks after surgery.Results. After normalization, comparison of OA and sham-operated samples showed 1,619 differentially expressed probe sets with changes in their levels of expression >1.5-fold, 722 with changes >2-fold, 135 with changes >4-fold, and 20 with changes of 8-fold. Dysregulated genes known to be involved in human OA included Mmp13, Adamts5, and Ptgs2, among others. Several dysregulated genes (e.g., Reln, Phex, and Ltbp2) had been identified in our earlier microarray study of hypertrophic chondrocyte differentiation. Other genes involved in cytokine and chemokine signaling, including Cxcr4 and Ccl2, were identified. Changes in gene expression were also observed in the contralateral knee, validating the sham operation as the appropriate control.Conclusion. Our results demonstrate that the animal model mimics gene expression changes seen in human OA, supporting the relevance of newly identified genes and pathways to early human OA. We propose new avenues for OA pathogenesis research and potential targets for novel OA treatments, including cathepsins and cytokine, chemokine, and growth factor signaling pathways, in addition to factors controlling the progression of chondrocyte differentiation.

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Section: Discussionmentioning

confidence: 99%

Global analyses of gene expression in early experimental osteoarthritis

Appleton¹,

Pitelka²,

Henry³

et al. 2007

Arthritis & Rheumatism

222

224

View full text Add to dashboard Cite

show abstract

“…We hypothesize that IL-22 and TNF-α represent the key combination of cytokines expressed by Th22 cells that unlocks the activation of keratinocytes, as in vitro cultures using either Th22 supernatants or a combination of IL-22 and TNF-α maximally induced the Th22 signature in keratinocytes, whereas anti-IL-22 did not fully block - and recombinant IL-22 alone was not sufficient to induce - expression of these genes. This dual key is a recurring scheme observed in the lymphoid regulation of tissue cells in inflammatory context, such as the regulation of epithelial cells by IL-17, which is only maximal in synergism with IFN-γ, IL-1, or TNF-α (42,43). In contrast to major effects on the innate immune response by keratinocytes in a proinflammatory context, IL-22 and TNF-α did not synergize in the enhanced wound healing clearly induced by Th22 cells.…”

Section: Figurementioning

confidence: 94%

Th22 cells represent a distinct human T cell subset involved in epidermal immunity and remodeling

et al. 2009

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Th subsets are defined according to their production of lineage-indicating cytokines and functions. In this study, we have identified a subset of human Th cells that infiltrates the epidermis in individuals with inflammatory skin disorders and is characterized by the secretion of IL-22 and TNF-α, but not IFN-γ, IL-4, or IL-17. In analogy to the Th17 subset, cells with this cytokine profile have been named the Th22 subset. Th22 clones derived from patients with psoriasis were stable in culture and exhibited a transcriptome profile clearly separate from those of Th1, Th2, and Th17 cells; it included genes encoding proteins involved in tissue remodeling, such as FGFs, and chemokines involved in angiogenesis and fibrosis. Primary human keratinocytes exposed to Th22 supernatants expressed a transcriptome response profile that included genes involved in innate immune pathways and the induction and modulation of adaptive immunity. These proinflammatory Th22 responses were synergistically dependent on IL-22 and TNF-α. Furthermore, Th22 supernatants enhanced wound healing in an in vitro injury model, which was exclusively dependent on IL-22. In conclusion, the human Th22 subset may represent a separate T cell subset with a distinct identity with respect to gene expression and function, present within the epidermal layer in inflammatory skin diseases. Future strategies directed against the Th22 subset may be of value in chronic inflammatory skin disorders.

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“…We can envision a couple of mechanisms (not mutually exclusive) by which TLR stimulation could influence angiogenic growth factor production in PBMCs: (i) a direct effect on VEGF and angiopoietin production and/or (ii) an indirect effect due to TLR-induced proinflammatory cytokine production. Proinflammatory cytokines, including tumor necrosis factor alpha (TNF-␣) and IL-17, are known inducers of VEGF proteins (13), and hence an indirect effect of TLR stimulation on angiogenic growth factor production cannot be excluded.…”

Section: Discussionmentioning

confidence: 99%

Toll-Like Receptor- and Filarial Antigen-Mediated, Mitogen-Activated Protein Kinase- and NF-κB-Dependent Regulation of Angiogenic Growth Factors in Filarial Lymphatic Pathology

et al. 2012

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c Filarial lymphatic pathology is of multifactorial origin, with inflammation, lymphangiogenesis, and innate immune responses all playing important roles. The role of Toll-like receptors (TLRs) in the development of filarial pathology is well characterized. Similarly, the association of pathology with elevated levels of plasma angiogenic factors has also been documented. To examine the association between TLR function and the development of lymphangiogenesis in filarial infections, we examined TLR-and filarial antigen-induced expression and production of various angiogenic growth factors. We demonstrate that TLR ligands

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IL-17, IL-1β and TNF-α stimulate VEGF production by dedifferentiated chondrocytes

Cited by 80 publications

References 38 publications

Global analyses of gene expression in early experimental osteoarthritis

Global analyses of gene expression in early experimental osteoarthritis

Th22 cells represent a distinct human T cell subset involved in epidermal immunity and remodeling

Toll-Like Receptor- and Filarial Antigen-Mediated, Mitogen-Activated Protein Kinase- and NF-κB-Dependent Regulation of Angiogenic Growth Factors in Filarial Lymphatic Pathology

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