Regulation of Activin A Expression in Mast Cells and Asthma: Its Effect on the Proliferation of Human Airway Smooth Muscle Cells

Cho, Seong H.; Yao, Zhengbin; Wang, Shen-Wu; Alban, Rodrigo F.; Barbers, Richard G.; French, Samuel W.; Oh, Chad K.

doi:10.4049/jimmunol.170.8.4045

Cited by 99 publications

(92 citation statements)

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“…Similar to other cytokines, activin A appears to be secreted in a second wave of mediators by mast cells, thus requiring de novo synthesis at a transcriptional level. 56,57 Moreover, activin A is only observed in the cytoplasm of IgE-activated bone marrow-derived murine mast cells, whereas in resting state this cytokine is not detected. 57 Mast cell degranulation is a process that is highly dependent on the induction of cytosolic Ca 2+ .…”

Section: Mast Cellsmentioning

confidence: 99%

“…56,57 Moreover, activin A is only observed in the cytoplasm of IgE-activated bone marrow-derived murine mast cells, whereas in resting state this cytokine is not detected. 57 Mast cell degranulation is a process that is highly dependent on the induction of cytosolic Ca 2+ . Similarly, the release of activin A is also dependent on the activation of the Ca 2+ -calmodulin-dependent enzymes, calcineurin and CamK, which synergize with p38 mitogenactivated protein kinase and c-Jun NH 2 -terminal kinase activity to further regulate activin bA subunit transcription.…”

Section: Mast Cellsmentioning

confidence: 99%

“…57 In this context, high levels of serum activin A have been found in patients with severe asthma and in bronchoalveolar lavage fluid from mice challenged with ovalbumin (OVA), 62,63 which correlated with increased p-Smad2 levels in bronchial biopsies. 21 Recent data have shown that activin A production can also be induced by IL-13, a cytokine involved in mucus production, which is a characteristic feature of asthma pathogenesis.…”

Section: Mast Cellsmentioning

confidence: 99%

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When versatility matters: activins/inhibins as key regulators of immunity

Alemán-Muench

Soldevila

2011

Immunol Cell Biol

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Activins and inhibins are members of the transforming growth factor-b superfamily that have been considered crucial regulators of cell processes, such as differentiation, proliferation and apoptosis, in different cell types. Initial studies about the function of activin A in the immune system focused on the regulation of hematopoiesis in the bone marrow under homeostatic and inflammatory conditions. Recent data provide a more comprehensive understanding about the role of activins/inhibins in the immune system. Novel findings included in this review point out the important requirement of activin/inhibin signaling to maintain the balance between homeostatic and inflammatory signals that are required for the optimal development and function of immune cells. The purpose of this review is to highlight the versatile nature of activins/inhibins as key regulators of both the innate and adaptive immune responses. Keywords: activin; inhibin; inflammation; immune cells; immunity; tolerance Activins and inhibins are members of the transforming growth factor-b (TGF-b) superfamily that were initially described as regulators of reproductive processes in mammals, and were first named after their positive and negative effect in the release of follicle-stimulating hormone from the pituitary gland, respectively. 1 These dimeric ligands have been shown to modulate a variety of cellular functions such as apoptosis, proliferation, differentiation, cellular migration, among others. 2,3 Activin A (bA/bA) is the best-characterized ligand of this subfamily, although there are other bioactive forms, activin B (bB/bB) and activin AB (bA/bB), which differ in their potency and cellular function. 4 Activin A is a molecule with pleiotropic functions, which shares with TGF-b the SMAD2/3 canonical signaling pathway (reviewed by Shi and Massague 5 ) but uses distinct type II (ActRIIs) and type I (ALK2, ALK4 and ALK7) receptors. [6][7][8][9] The biological function of activins can be blocked by follistatin (FS), a glycoprotein that binds activin A with high affinity, functioning as a ligand trap. 10 On the other hand, inhibins are heterodimers formed by uncommon a-and b-subunits and exist in two isoforms, inhibin A (a/bA) and B (a/bB). Inhibins have been shown to antagonize activinmediated functions by a mechanism that involves binding to b-glycan (TGFbRIII) and formation of a ternary complex with ActRIIs. As a consequence, activin type I receptors (ALK4 and ALK2) are excluded from the receptor complex, leading to the inhibition of SMADmediated signaling. 3,[11][12][13][14] Despite the fact that inhibins have been classically considered as activin antagonists, there is evidence showing that they do not always antagonize activin-mediated functions in several cell types, suggesting the existence of an independent inhibinmediated signaling pathway. 3 Compelling evidence has shown that activins also regulate various non-reproductive processes, such as mesoderm induction, liver proliferation, skin morphogenesis, erythropoiesis, bone formation, neu...

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Section: Mast Cellsmentioning

confidence: 99%

Section: Mast Cellsmentioning

confidence: 99%

Section: Mast Cellsmentioning

confidence: 99%

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When versatility matters: activins/inhibins as key regulators of immunity

Alemán-Muench

Soldevila

2011

Immunol Cell Biol

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“…There is evidence that activin can both have an inhibitory or proliferative effect on cell proliferation; dependent on the cell type (41)(42)(43)(44)(45)(46)(47). In vivo studies have shown that FST knockout mice died soon after birth due to a variety of skeletal and cutaneous defects amongst other defects seen in the activin-deficient mice (48).…”

Section: Abstract Follistatin (Fst) As a Single-chain Glycosylated mentioning

confidence: 99%

Clinical and Therapeutic Implications of Follistatin in Solid Tumours

Shi

Resaul

Owen

et al. 2016

CGP

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Abstract. Follistatin (FST) Follistatin (FST), which was first isolated from porcine and bovine follicular fluid (1, 2), was initially described as a protein involved in the regulation of the secretion of folliclestimulating hormone. This monomeric glycosylated polypeptide chain is encoded by a single gene located on the long arm chromosome 5q11.2 (3), which through alternative splicing may be transcribed into the mRNA precursors, FST317 and FST344. From these precursors, three major FST isoforms may be produced, namely FST288 (from pre-FST317), FST315 (from pre-FST344) and a third FST isoform, FST303, produced from the post-translational truncation of the FST315 C-terminus. These three main FST isoforms can also be glycosylated to yield six further FST isoforms that were previously identified in bovine (4) and porcine (5, 6) follicular fluid. At the core, all FST isoforms contain a 63 residue N-terminal domain and three follistatin domains, termed FSD1, FSD2 and FSD3. These domains comprise 73-77 amino acid residues and are characterised by an arrangement of 10 conserved cysteine residues (7). Both FST288 and FST315 are differentially expressed in human tissues (6-9). FST315 is the predominant isoform, whilst the FST288 isoform accounts for less than 5% of the encoded mRNA (10, 11). Some molecules such as activin, transforming growth factor-beta (TGFβ), forkhead domain transcription factor L2 (12, 13), gonadotropin-releasing hormone (14), zinc finger protein (GLI2) (15), dexamethasone (16), androgens (17), activators of winglessrelated integration site (WNT) signalling (18, 19) and 1,25-dihydroxyvitamin D (20) have been shown to regulate the transcription of the FST gene. In addition, down-regulation of FST gene expression by peroxisome proliferator-activated receptor gamma (PPARγ) or the transcription factor epiprofin (21, 22) has been shown.As an antagonist of TGFβ superfamily member activin, FST seems to primarily function in relation to the role that activin plays. Along with FST, activin acts as a pleiotropic growth factor system, which is involved in proliferation, differentiation, and apoptosis of a number of cell types (23-28). As such, the functions of the FST isoforms are therefore linked to their binding affinity for activin (6,10,11,(29)(30)(31)(32)(33)(34)(35)(36)(37). In fact, this critical binding and neutralisation of activin, either partial or complete, is based on the order of at least two of the FST cysteine domains and its Nterminal (38), conferring a difference in affinities for activin between the FST isoforms. The binding complex between activin and FST generally occurs in a 1:2 ratio, where the two FST molecules, connected C-terminus to N-425

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“…Inflammatory stimuli seem to induce the production of activin A by various cell types, including peritoneal macrophages (28), monocytes (29), mast cells (30), or Th2 cells (27,31). Indeed, activin A is released into the circulation as early as 1 h after LPS injection (32,33).…”

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confidence: 99%