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

Abstract

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...

Activin-A enhances mTOR signaling to promote aberrant chondrogenesis in fibrodysplasia ossificans progressiva

“…In FOP pathology, the mutation of ACVR1 appears to deviate this fine-tuned tissue homeostasis mechanism. Activin-A is strongly expressed in wounded regions and promotes the regeneration of damaged tissue (64)(65)(66). In FOP, however, we found what we believe to be a new signaling pathway for Activin-A that initiates HO formation by mistransducing BMP signaling.…”

Peripheral Blood Mononuclear Cell Immunophenotyping in Fibrodysplasia Ossificans Progressiva Patients: Evidence for Monocyte DNAM1 Up‐regulation

“…Activin A is a ligand member of the transforming growth factor-beta superfamily rapidly released into the circulation during inflammation and is considered a critical mediator of inflammation and immunity. In particular, it regulates growth and maturation of mast cells, monocyte/macrophage differentiation, the interaction between NK and dendritic cells (43) and is stimulated by inflammatory cytokines, Toll-like receptor ligands, and oxidative stress (44,45). Our phenotypic characterization shows that in FOP patients there is an increase of DNAM1 expression in subpopulations of monocytes, which raises the hypothesis of possible functional consequences in this cell type that should be further investigated.…”

Seminal fluid factors regulate activin A and follistatin synthesis in female cervical epithelial cells

“…A C C E P T E D ACCEPTED MANUSCRIPT 5 generation of regulatory T cells [24], INHBA is emerging as a key immune-regulatory and toleranceinducing cytokine [13,25]. 70 INHBA signals via the classical TGFB (SMAD2/3) signalling pathway, however unlike TGFB, it binds to distinct type II (ActIIRA and ActIIRB) and type I (ALK2, ALK4 and ALK7) receptors [26][27][28].…”

“…INHBA and FST regulation of cytokine synthesis in Ect1 cellsGiven their induction by seminal plasma in Ect1 cells and their known roles as regulators of inflammation[25], we next assessed whether INHBA and FST regulate pro-inflammatory cytokines induced by seminal plasma in Ect1 cells. Ect1 cells were incubated with recombinant INHBA or FST, medium alone, or 10% seminal plasma.…”