Physiologic responses to hypoxia and implications for hypoxia‐inducible factors in the pathogenesis of rheumatoid arthritis

Distler, J�rg H. W.; Wenger, Roland H.; Gassmann, Max; Kurowska, Weronika; Astrid, Hirth; Gay, Steffen; Distler, Oliver

doi:10.1002/art.11425

Cited by 102 publications

(111 citation statements)

References 142 publications

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“…Pathological conditions that damage local microvasculature may also result in hypoxia. Moreover, a recent study has also shown that infiltrating T cells in synovia of patients with rheumatoid arthritis contain high levels of HIF-1␣ (9), consistent with an important role for hypoxia in the inf lamed rheumatoid joint (10).…”

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confidence: 76%

Hypoxia inducible factor 1α regulates T cell receptor signal transduction

Neumann

Yang

Biju

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

106

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Low oxygen pressures exist in many solid tissues, including primary and secondary lymphoid organs. One key element in cellular adaptation to hypoxia is induced expression of hypoxia inducible factor (Hif) 1␣. Here, we have examined the effect of Hif-1␣, isolated from the myriad other effects of hypoxia, on T cell receptor (TCR) signaling in thymocytes. Because pVHL (von Hippel-Lindau protein) directs the proteolysis of Hif-1␣ under ''normoxic'' conditions, we achieved constitutive stabilization of Hif-1␣ through thymic deletion of Vhlh and reversed Hif-1␣ stabilization with double deletion of Vhlh and Hif-1␣. We found that constitutive activity of Hif-1␣ resulted in diminished Ca 2؉ response upon TCR crosslinking despite equivalent activation of phospholipase C␥1, normal intracellular Ca 2؉ stores, and normal entry of Ca 2؉ across the plasma membrane. Altered Ca 2؉ response was instead due to accelerated removal of Ca 2؉ from the cytoplasm into intracellular compartments, which occurred in association with Hif-1␣-dependent overexpression of the calcium pump SERCA2 (sarcoplasmic͞ endoplasmic reticulum calcium ATPase 2). These data suggest a unique mechanism for control of TCR signaling through Hif-1␣, which may be operative at the physiologic oxygen tensions seen in solid lymphoid organs.calcium ͉ lymphocytes

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mentioning

confidence: 76%

Hypoxia inducible factor 1α regulates T cell receptor signal transduction

Neumann

Yang

Biju

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

106

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“…Hypoxia occurs in cardiovascular, hematological, and pulmonary disorders, arthritic joints, atherosclerosis plaques, and ischemic wounds (28)(29)(30)(31). Previous reports showed that H/R induced the generation of a burst of reactive oxygen species, which could activate NF-kB (1,4).…”

Section: Discussionmentioning

confidence: 99%

Enhancement of CCL15 Expression and Monocyte Adhesion to Endothelial Cells (ECs) after Hypoxia/Reoxygenation and Induction of ICAM-1 Expression by CCL15 via the JAK2/STAT3 Pathway in ECs

Park

Lee

Kim

et al. 2013

The Journal of Immunology

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CCL15, a member of the CC chemokine family, is a potent chemoattractant for leukocytes and endothelial cells (ECs). Given that chemokines play key roles in vascular inflammation, we investigated the effects of hypoxia/reoxygenation (H/R) on expression of human CCL15 and a role of CCL15 in upregulating ICAM-1 in ECs. We found that exposure of ECs to H/R increased expression of CCL15 and ICAM-1, which resulted in an increase in monocyte adhesivity to the ECs. Further studies revealed that knockdown of CCL15 or CCR1 attenuated expression of ICAM-1 in ECs after H/R, suggesting that expression of ICAM-1 is upregulated by CCL15. Stimulation of ECs with CCL15 significantly increased expression of ICAM-1 predominantly via the CCR1 receptor. We observed that phosphorylation of JAK2 and STAT3 was stimulated by CCL15 treatment of ECs. Results from reporter and chromatin immunoprecipitation assays revealed that CCL15 activates transcription from the IFN-γ activation site promoter and stimulates binding of STAT3 to the ICAM-1 promoter. Our data also showed that CCL15 increased cell adhesion of human monocytes to ECs under static and shear-stress conditions. Pretreatment of these cells with inhibitors for JAK, PI3K, and AKT prevented the CCL15-induced expression of ICAM-1 and monocyte adhesion to ECs, suggesting the involvement of those signaling molecules in ICAM-1 gene activation by CCL15. The results suggest that CCR1 and its ligands may be a potential target for treating inflammatory diseases involving upregulation of cell adhesion molecules.

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“…This is underlined by our results in dermal fibroblasts, which identified hypoxia-induced molecules with a role in such diverse biologic processes as angiogenesis, proliferation, cellular metabolic pathways, and extracellular matrix accumulation. Cell culture studies performed under normoxic conditions at 20% oxygen clearly do not resemble the hypoxic environment present in vivo in SSc tissues (7). Thus, the interference with multiple hypoxia-driven pathways is overlooked with normoxic culture conditions and has not been taken into account in the majority of in vitro experiments in the past.…”

Section: Discussionmentioning

confidence: 99%

Hypoxia‐induced increase in the production of extracellular matrix proteins in systemic sclerosis

Distler

Jüngel²,

Pileckytė

et al. 2007

Arthritis & Rheumatism

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169

141

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Objective. Insufficient angiogenesis with tissue ischemia and accumulation of extracellular matrix are hallmarks of systemic sclerosis (SSc). Based on the severely decreased oxygen levels in the skin of patients with SSc, we aimed to investigate the role of hypoxia in the pathogenesis of SSc.Methods. Subtractive hybridization was used to compare gene expression in dermal fibroblasts under hypoxic and normoxic conditions. Dermal fibroblasts were further characterized by exposure to different concentrations of oxygen and for different time periods as well as by interference with hypoxia-inducible factor 1␣ (HIF-1␣). The systemic normobaric hypoxia model in mice was used for in vivo analyses.Results. Several extracellular matrix proteins and genes involved in extracellular matrix turnover, such as thrombospondin 1, pro␣2(I) collagen, fibronectin 1, insulin-like growth factor binding protein 3, and transforming growth factor ␤-induced protein, were induced by hypoxia in SSc and healthy dermal fibroblasts. The induction of these genes was time-and dose-dependent. Experiments with HIF-1␣-knockout mouse embryonic fibroblasts, deferoxamine/cobalt ions as chemical stabilizers of HIF-1␣, and HIF-1␣ small interfering RNA consistently showed that extracellular matrix genes are induced in dermal fibroblasts by HIF-1␣-dependent, as well as HIF-1␣-independent, mechanisms. Using the systemic normobaric hypoxia mouse model, we demonstrated that dermal hypoxia leads to the induction of the identified extracellular matrix genes in vivo after both short exposure and prolonged exposure to hypoxia.Conclusion. These data show that hypoxia contributes directly to the progression of fibrosis in patients with SSc by increasing the release of major extracellular matrix proteins. Targeting of hypoxia pathways might therefore be of therapeutic value in patients with SSc.

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Physiologic responses to hypoxia and implications for hypoxia‐inducible factors in the pathogenesis of rheumatoid arthritis

Cited by 102 publications

References 142 publications

Hypoxia inducible factor 1α regulates T cell receptor signal transduction

Hypoxia inducible factor 1α regulates T cell receptor signal transduction

Enhancement of CCL15 Expression and Monocyte Adhesion to Endothelial Cells (ECs) after Hypoxia/Reoxygenation and Induction of ICAM-1 Expression by CCL15 via the JAK2/STAT3 Pathway in ECs

Hypoxia‐induced increase in the production of extracellular matrix proteins in systemic sclerosis

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