Activation of paracrine TGF‐β1 signaling upon stimulation and degranulation of rat serosal mast cells: a novel function for chymase

Lindstedt, Ken A.; Wang, Yenfeng; Shiota, Naotaka; Saarinen, Jyrki; Hyytiäinen, Marko; Kokkonen, Jorma; Keski‐Oja, Jorma; Kovanen, Petri T.

doi:10.1096/fj.00-0273com

Cited by 180 publications

(140 citation statements)

References 49 publications

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“…Potentially, the action of mast cell‐released proteases could either lead to proteolytic activation of cytokines, or to cytokine degradation and destroyed biological activity. In accordance with the former possibility, there are reports suggesting that mast cell serine proteases can proteolytically activate certain cytokines 31, 32, 33 and chemokines 34, 35. Conversely, protease‐dependent degradation of cytokines by human mast cells has previously been demonstrated 6, 12.…”

Section: Discussionsupporting

confidence: 56%

IL‐6 and IL‐17A degradation by mast cells is mediated by a serglycin:serine protease axis

Waern

Karlsson

Pejler³

et al. 2015

Immunity, Inflammation and Disease

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Mast cells contain large amounts of fully active proteases that are stored in complex with serglycin proteoglycan in their secretory granules. Upon degranulation, such serglycin:protease complexes are released to the extracellular space and can potentially have an impact on the local inflammatory reaction, either through direct effects of serglycin proteoglycan or through effects mediated by its bound proteases. The objective of this study was to address this scenario by investigating the possibility that serglycin‐associated proteases can regulate levels of pro‐inflammatory cytokines. Indeed, we show here that activated cultured peritoneal mast cells from wild type mice efficiently reduced the levels of exogenously administered IL‐6 and IL‐17A, whereas serglycin‐deficient mast cells lacked this ability. Furthermore, our data suggest that the reduction of IL‐6 and IL‐17A concentrations is due to proteolytic degradation mediated by serglycin‐dependent serine proteases. Moreover, we show that activated mast cells have the capacity to release IL‐6 and that the levels of this cytokine in supernatants were markedly higher in cultures of serglycin‐deficient versus serglycin‐sufficient mast cells, suggesting that serglycin‐dependent serine proteases also participate in the regulation of endogenously produced IL‐6. In summary, although the general consensus is that mast cells have a pathogenic impact on inflammatory settings, this study identifies a role for a mast cell‐derived serglycin:serine protease axis in down‐regulating levels of major inflammatory cytokines. These findings support the notion that mast cells could have a dual role in inflammatory settings, by both being able to secrete pathogenic compounds and being able to regulate their levels after release.

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Section: Discussionsupporting

confidence: 56%

IL‐6 and IL‐17A degradation by mast cells is mediated by a serglycin:serine protease axis

Waern

Karlsson

Pejler³

et al. 2015

Immunity, Inflammation and Disease

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show abstract

“…In some systems CD44 has been shown to act as a docking site for proteolytically active MMP-9 (57); immobilized active MMP-9 then cleaves latent TGF-␤ to its active form (58). Interestingly, while mast cell-derived chymase has been shown to release latent TGF-␤ from epithelial cell cultures (59), it has a variable ability to activate latent TGF-␤ directly (51,59,60). One could speculate that local release of chymase by mast cells, and potentially by ASM cells (61), activates MMP-9 and induces the release of latent TGF-␤, which, in turn, is activated by either MMP-9 or chymase.…”

Section: Discussionmentioning

confidence: 99%

Mast Cell Chymase Modifies Cell-Matrix Interactions and Inhibits Mitogen-Induced Proliferation of Human Airway Smooth Muscle Cells

Lazaar

Plotnick

Kucich

et al. 2002

The Journal of Immunology

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The hallmarks of chronic, severe asthma include prominent airway inflammation and airway smooth muscle (ASM) hypertrophy and hyperplasia. One of the factors that contribute to the injury and repair process within the airway is activation of proteases and turnover of extracellular matrix components. Mast cells, which are present in increased numbers in the asthmatic airway, are a rich source of the neutral protease chymase, which can degrade several basement membrane components. Recent data suggest that proteases also play a critical role in regulating the expression of CD44, the primary receptor for the matrix glycosaminoglycan hyaluronan. In this study we investigated the effects of chymase treatment on human ASM cell function. We found that chymase degraded the smooth muscle cell pericellular matrix. This was accompanied by an increased release of fibronectin and soluble CD44, but not soluble ICAM-1 or soluble hyaluronan, into the conditioned medium. In addition, chymase inhibited T cell adhesion to ASM and dramatically reduced epidermal growth factor-induced smooth muscle cell proliferation. These data suggest that the local release of mast cell chymase may have profound effects on ASM cell function and airway remodeling.

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“…Lindstedt et al (18) recently reported that TGF-␤1 was stored as latent form in secretary granules of mast cells, that was rapidly released and converted into active form by co-released chymase1 upon mast cell activation. It is therefore possible that LPS induced endogenous TGF-␤1, which could then suppress mast cell responses to LPS in an autocrine manner.…”

Section: Neutralizing Tgf-␤ Activity Enhances Lps-induced Cytokine Prmentioning

confidence: 99%

Smad3 Deficiency in Mast Cells Provides Efficient Host Protection against Acute Septic Peritonitis

Kanamaru¹,

Sumiyoshi²,

Ushio³

et al. 2005

The Journal of Immunology

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Mast cells play an important role in innate immunity as well as in allergic reaction. However, regulatory mechanisms underlying mast cell-mediated innate immune responses remain largely unknown. Here we determined whether Smad3, a major signal transducer of TGF-β, regulates innate immune response by mast cells against Gram-negative bacteria. Bone marrow-derived mast cells (BMMC) obtained from Smad3 null mutant mice showed augmented capacity to produce proinflammatory cytokines upon stimulation with a Gram-negative bacteria-associated product, LPS. In acute septic peritonitis model induced by cecal ligation and puncture, mast cell-deficient W/Wv mice reconstituted with Smad3 null BMMC had significantly higher survival rate than W/Wv mice reconstituted with wild-type BMMC, which was associated with higher production of proinflammatory cytokines in the peritoneal cavity. These in vitro and in vivo results suggest that Smad3 in mast cells functions as inhibitory for mast cell-mediated innate immune response against Gram-negative bacteria. Suppression of Smad3 expression in mast cells may thus have therapeutic potential for Gram-negative bacterial infection such as acute septic peritonitis by augmenting innate immune responses of mast cells.

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Activation of paracrine TGF‐β1 signaling upon stimulation and degranulation of rat serosal mast cells: a novel function for chymase

Cited by 180 publications

References 49 publications

IL‐6 and IL‐17A degradation by mast cells is mediated by a serglycin:serine protease axis

IL‐6 and IL‐17A degradation by mast cells is mediated by a serglycin:serine protease axis

Mast Cell Chymase Modifies Cell-Matrix Interactions and Inhibits Mitogen-Induced Proliferation of Human Airway Smooth Muscle Cells

Smad3 Deficiency in Mast Cells Provides Efficient Host Protection against Acute Septic Peritonitis

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