Decorin Reverses the Repressive Effect of Autocrine-Produced TGF-β on Mouse Macrophage Activation

Comalada, Mònica; Cardó, Marina; Xaus, Jordi; Valledor, Annabel F.; Lloberas, Jorge; Ventura, Francesc; Celada, Antonio

doi:10.4049/jimmunol.170.9.4450

Cited by 58 publications

(50 citation statements)

References 45 publications

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“…Two mechanisms for decorin inhibition of TGF-␤ have been reported, although neither was demonstrated in cartilage. In macrophages, decorin reverses the inhibitory effect of TGF-␤ by binding to it and preventing its interaction with the cell surface (34). It is likely that decorin blocks interaction of TGF-␤ with its cell-surface receptor(s), but this has not been confirmed.…”

Section: Discussionmentioning

confidence: 89%

Mechanisms for Asporin Function and Regulation in Articular Cartilage

Nakajima

Kizawa

Saitoh

et al. 2007

Journal of Biological Chemistry

143

109

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Osteoarthritis (OA), the most prevalent form of skeletal disease, represents a leading cause of disability following middle age. OA is characterized by the loss of articular cartilage; however, the details of its etiology and pathogenesis remain unclear. Recently, we demonstrated a genetic association between the cartilage extracellular matrix protein asporin and OA (Kizawa, H., Kou, I., Iida, A., Sudo, A., Miyamoto, Y., Fukuda, A., Mabuchi, A., Kotani, A., Kawakami, A., Yamamoto, S., Uchida, A., Nakamura, K., Notoya, K., Nakamura, Y., and Ikegawa, S. (2005) Nat. Genet. 37, 138 -144). Furthermore, we showed that asporin binds to transforming growth factor-␤ (TGF-␤), a key cytokine in OA pathogenesis, and inhibits TGF-␤-induced chondrogenesis. To date, functional data for asporin have come primarily from mouse cell culture models of developing cartilage rather than from human articular cartilage cells, in which OA occurs. Here, we describe mechanisms for asporin function and regulation in human articular cartilage. Asporin blocks chondrogenesis and inhibits TGF-␤1-induced expression of matrix genes and the resulting chondrocyte phenotypes. Small interfering RNAmediated knockdown of asporin increases the expression of cartilage marker genes and TGF-␤1; in turn, TGF-␤1 stimulates asporin expression in articular cartilage cells, suggesting that asporin and TGF-␤1 form a regulatory feedback loop. Asporin inhibits TGF-␤/Smad signaling upstream of TGF-␤ type I receptor activation in vivo by co-localizing with TGF-␤1 on the cell surface and blocking its interaction with the TGF-␤ type II receptor. Our results provide a basis for elucidating the role of asporin in the molecular pathogenesis of OA.

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Section: Discussionmentioning

confidence: 89%

Mechanisms for Asporin Function and Regulation in Articular Cartilage

Nakajima

Kizawa

Saitoh

et al. 2007

Journal of Biological Chemistry

143

109

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“…This result might be explained by the finding that such an extracellular matrix component as decorin, which is presented in AM stroma (Meinert et al, 2001), induces mRNA expression of IFN-α and enhances IFN-γ dependent macrophage activation, meanwhile increasing the production of IFN-α and iNOS (Comalada et al, 2003). This interpretation also partially explains the synergistic action of AM and IFN-γ in producing more NO and IFN-α.…”

Section: Discussionmentioning

confidence: 96%

Amniotic membrane induces apoptosis of interferon-γ activated macrophages in vitro

Kawakita

et al. 2006

Experimental Eye Research

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Amniotic membrane (AM) used as a temporary or permanent graft for ocular surface reconstruction has a potent anti-inflammatory effect. We would like to investigate the mechanism whereby AM induces macrophage apoptosis in vitro. Mouse macrophages, Raw 264.7 cells, were cultured on plastic, type I collagen, corneal stromal slice or AM stromal matrix in serum-free medium with or without interferon-γ (IFN-γ). Cells were stained by LIVE/DEAD assay, Hoechst-33342, and TUNEL assay for cell death and apoptosis. Cell lysates and conditioned media were analysed by Cell Death Detection ELISA assay for quantitation of apoptosis. Conditioned media were also analysed by Griess assay for the nitrite concentration and ELISA assay for tumour necrosis factor alpha (IFN-α) concentration. Lysates of cells were subjected to Western blot analyses of IKK-α, IKK-β, p65 (RelA) subunit of nuclear factor κB (NF-κB), total Akt, phospho-Akt (Ser473), and phospho-FKHR (Thr24)/phosphor-FKHRL1 (Thr32). At 48 hr after cultivation, cells showed a low level of apoptosis when cultured on plastic, type I collagen and corneal stromal slice with or without IFN-γ and on AM without IFN-γ. Nevertheless, cells showed a significant increase of apoptosis when cultured on AM with IFN-γ activation, and this phenomenon became apparent only after 48 hr. IFN-γ-activated macrophages on plastic continuously produced nitric oxide (NO) and IFN-α during 72 hr culturing. In contrast, there was no NO and IFN-α production after 48 hr culture on AM. NO inhibitors, L-NMMA and L-NIL, attenuated NO production of IFN-γ-activated macrophages on AM, while apoptosis was not decreased accordingly. Expression of IKK-α, IKK-β, p65 (RelA) subunit of NF-κB total Akt, phosopho-Akt (Ser473), and phospho-FKHR (Thr24)/FKHRL1 (Thr32) was all down-regulated in IFN-γ-activated macrophages cultured on AM. In conclusion, AM stromal matrix induces apoptosis of IFN-γ activated, but not non-activated macrophages, not through the generation of NO, but instead by down-regulating anti-apoptotic NF-κB and Akt-FKHR signalling pathways.

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“…[33][34][35][36] It is therefore noteworthy that decorin has been shown to act as a proinflammatory factor and is produced at sites of inflammation. 18,[37][38][39][40][41] In contrast, Decorin, obesity and type 2 diabetes K Bolton et al decorin has also been reported to bind and inhibit the proinflammatory activity of the complement protein C1q 42 and has been hypothesized to antagonize C1q-induced insulin resistance in adipose tissue that is associated with obesity. 16 These observations indicate that decorin may play a role in inflammation associated with obesity in adipose tissue; however, this is likely to be a complex interaction between pro-and anti-inflammatory activities.…”

Section: Discussionmentioning

confidence: 99%

Decorin is a secreted protein associated with obesity and type 2 diabetes

et al. 2008

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Objective: To characterize the expression of the small leucine-rich glycoprotein decorin in adipose tissue. Design: Real-time PCR was used to measure decorin gene expression in adipose tissue from normal glucose tolerant (NGT), impaired glucose tolerant and type 2 diabetic (T2D) Psammomys obesus. Adipose tissue was fractionated to determine which cells were responsible for decorin expression. The location of decorin protein expression in adipose tissue was determined using immunohistochemistry. Real-time PCR was used to measure decorin mRNA levels in human adipose tissue from 16 insulinsensitive, 16 insulin-resistant and 6 T2D human subjects. Circulating plasma decorin concentrations were measured by enzymelinked immunosorbent assay in 145 NGT and 141 T2D human individuals from a large-scale epidemiological study in Mauritius. Results: Decorin mRNA was found to be highly expressed in adipose tissue, and decorin gene expression was significantly higher in visceral than that in subcutaneous adipose tissue depots in both P. obesus and human subjects (P ¼ 0.002 and P ¼ 0.001, respectively). Decorin mRNA was predominantly expressed by stromal/vascular cells of adipose tissue, and decorin protein in adipose tissue was primarily detected adjacent to blood vessels. Circulating plasma decorin levels in humans were elevated by 12% in T2D (P ¼ 0.049) compared to NGT subjects. There was a significant independent correlation between plasma decorin levels and waist-to-hip ratio (WHR, P ¼ 0.024). In male subjects, plasma decorin levels were significantly correlated with WHR (P ¼ 0.006), and fasting and 2-h glucose levels in an oral glucose tolerance test (P ¼ 0.027 and P ¼ 0.001, respectively). Conclusions: Decorin expression in adipose tissue was markedly upregulated in the obese state and may therefore play a role in adipose tissue homeostasis or in pathophysiology associated with obesity.

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Decorin Reverses the Repressive Effect of Autocrine-Produced TGF-β on Mouse Macrophage Activation

Cited by 58 publications

References 45 publications

Mechanisms for Asporin Function and Regulation in Articular Cartilage

Mechanisms for Asporin Function and Regulation in Articular Cartilage

Amniotic membrane induces apoptosis of interferon-γ activated macrophages in vitro

Decorin is a secreted protein associated with obesity and type 2 diabetes

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