&p.1:Abstract Activin A and inhibin A, first isolated from the ovary, are dimeric proteins able to modulate pituitary FSH secretion. Inhibin A is a heterodimer composed of one α-subunit and one βA-subunit (α-βA), while activin A is a homodimer of the βA-subunit (βA-βA). Their identification in several tissues has suggested that they have numerous physiological functions, acting as either paracrine or autocrine factors. The aim of this study was to evaluate the expression of activin A and inhibin A in normal endocrine cells and in 70 endocrine tumours from different sites in the gastro-entero-pancreatic system, using specific monoclonal antibodies directed against the α- and βA-subunits of inhibin/activin. Immu- noreactivity for the βA-subunit, but not for the α-sub- unit, was observed in normal G, EC, and GIP cells of the antrum and duodenum, and in pancreatic A cells. βA- subunit expression was observed in G cell and A cell tu- mours, and in a few insulinomas and ileal EC cell car- cinoids. The α-subunit was found in rare cells in 7 of the 70 tumours and was colocalized with the βA-subunit in only 1 tumor. Specific types of endocrine cells from the gut and pancreas appear to produce only activin A, a possible paracrine or autocrine modulator. Activin A is mainly produced by tumours derived from endocrine cells that normally express it. &kwd:Key words Activin A · Inhibin A · Endocrine tumors · Digestive system · Immunohistochemistry&bdy: Introduction Activin and inhibin are both dimeric proteins first isolated from the ovary and able to modulate FSH release from the pituitary in a long-loop endocrine fashion [13, 20, 41]. Both inhibins and activins are sulphydryl-linked dimers comprising two of three distinct inhibin protein subunits (α, βA, βB). Inhibins are heterodimers composed of one α-subunit and one β-subunit (either βA or βB), producing inhibin A (α-βA) or inhibin B (α-βB) [22, 39]. Activins consist of homodimers of any combination of the β-sub- units, resulting in activin A (βA-βA), activin AB (βA-βB), and activin B (βB-βB) [20, 41]. These proteins are mem- bers of the transforming growth factor-β (TGFβ) super- family, which includes multiple forms of TGFβ, müllerian inhibiting substance (MIS), the decapentaplegic gene complex of Drosophila, bone morphogenic proteins and the amphibian protein VG-1. Many of these growth fac- tors have been shown to have growth-promoting, growth- inhibiting, or both activities, depending on the current sta- tus of a particular cell [7, 23, 44, 45]. The identification of inhibin subunits in a wide variety of reproductive and non- reproductive tissues [25] has suggested that these peptides, in addition to regulating FSH biosynthesis and secretion in the pituitary, may have a greatly expanded biological role. These functions include the regulation of steroid produc- tion in the gonads and adrenal glands, and the modulation of cell growth and maturation in several tissues, both in the fetus and in the adult [13]. It has also been shown that many of these regulatory roles are exerted locally by a paracrine or autocrine mechanism [2, 5]. Activin signal- ling occurs via binding to heterotrimeric receptor complex with trensmembrane serine/threonine kinase activity [24]. A receptor with specific affinity for inhibin has not been identified; however, inhibin has been shown to bind to ac- tivin type II receptors, although with lower affinity than activin [13]. Activin action can also be regulated by two binding proteins. Follistatin binds activin with high-affini- ty, nearly irreversible kinetics and neutralizes activin when in complex form [34]. α2-Macroglobulin binds to activin or inhibin with its high capacity and low affinity, without S. La Rosa · S. Uccella · P. Billo · C. Facco · F. Sessa C. Capella ( ✉ ) 1 Department of Clinical Biological Sciences, University of Pavia at Varese, Varese, Italy Mailing address: 1 Servizio di Anatomia Patologica, Ospedale Multizonale, Viale Borri, 57, I-21100 Varese, Italy Tel.: +39-332-278 231, FAX: +39-332-278 599&/fn-block: Virchows Arch (1999) 434:29–36 © Springer-Verlag 1999 ORIGINAL ARTICLE &roles:Stefano La Rosa · Silvia Uccella · Paola Billo Carla Facco · Fausto Sessa · Carlo Capella Immunohistochemical localization of α- and βA-subunits of inhibin/activin in human normal endocrine cells and related tumors of the digestive system &misc:Received: 17 July 1998 / Accepted: 30 July 1998