The Plasmacytoma Growth Inhibitor Restrictin-P Is an Antagonist of Interleukin 6 and Interleukin 11

Abstract

A stromal protein, designated restrictin-P, that specifically kills plasma-like cells was purified to homogeneity and shown to be identical with activin A. The specificity to plasma-like cells stemmed from the ability of restrictin-P/activin A to competitively antagonize the proliferation-inducing effects of interleukin (IL) 6 and IL-11. Restrictin-P further interfered with the IL-6-induced secretion of acute phase proteins by HepG2 human hepatoma cells and with the IL-6-mediated differentiation of M1 myeloblasts. A competition binding assay indicated that restrictin-P did not interfere with the binding of IL-6 to its receptor on plasma-like cells, suggesting that it may act by intervening in the signal transduction pathway of the growth factor. Indeed, concomitant addition of restrictin-P and IL-6 to cytokinedeprived B9 hybridoma cells was followed by sustained overexpression of junB gene until cell death occurred, while IL-6 alone caused a transient increase only. This altered response to IL-6 stimulation was accompanied by a moderate increase in STAT protein activation. Thus, in this study, we identified the plasmacytoma growth inhibitor, restrictin-P, as being activin A of stromal origin. It is shown that activin A is an antagonist of IL-6-induced functions and that it modifies the IL-6 signaling pattern.

Involvement of p21WAF1/Cip1, CDK4 and Rb in activin A mediated signaling leading to hepatoma cell growth inhibition

“…STAT proteins may therefore not be involved in mediating the activin A growth inhibitory signal in this system. Activin A was ®rst studied as an inducer of follicle stimulating hormone (FSH) release (Vale et al, 1986;Ling et al, 1986), and was later found to be a pleiotropic cytokine exhibiting a variety of di erent functions (Murata et al, 1988;Fujimoto et al, 1991;Asashima et al, 1990;Smith et al, 1990;van den Eijnder et al, 1990;Thomsen et al, 1990;Matzuk et al, 1995;Zipori et al, 1986;Brosh et al, 1995). Included among its biological functions are also induction of growth inhibition and cell death.…”

“…It was further found, using the yeast twohybrid system, that the p21 ras farnesyltransferase (FNTA) a subunit, is bound to the TGFb and activin type I receptors, and is phosphorylated and released intracellularly upon ligand binding (Wang et al, 1996). A common response to activin A signaling is transcriptional activation of the early response gene junB (Hashimoto et al, 1993;Brosh et al, 1995). p21 ras (Whitman and Melton, 1992;Mulder and Morris, 1992) and other components of the MEK, MAPK cascades as well as G proteins (Murthy et al, 1988) have been implicated in a variety of cell systems as targets of TGFb family members.…”

Interleukin‐6: Structure‐function relationships

“…gp130 binders such as OSM (Sporeno et al, 1994) and neutralizing gp130 mAbs (Hibi et al, 1990;Taga et al, 1992;Saito et al, 1993;Chevalier et al, 1996), as well as soluble forms of gp130 (Narazaki et al, 1993) may be less specific due to their potential interference with the activities of the other members of the IL-6 family of cytokines. Activin A, a stroma-derived antagonist of IL-6 and IL-1 1, may act by interfering with intracellular signaling induced via gp130 (Brosh et al, 1995).…”

Direct Effects of Activin A on the Activation of Mouse Macrophage RAW264.7 Cells

“…Activin A, a multifunctional factor of the transforming growth factor-beta (TGF-) superfamily, is mainly produced by microglia and macrophages, and both its anti-inflammatory and pro-inflammatory activities are related to macrophage functions (3)(4)(5)(6). As an anti-inflammatory factor, activin A is involved in regulation of acute phase response in inflammatory diseases via autocrine and paracrine manner, and also acts as an antagonist of interleukin (IL)-6 and IL-11, which can be produced by macrophages (5)(6)(7). Recently our studies have demonstrated that activin A could down-regulate the phagocytosis of lipopolysaccharide (LPS)-activated mouse peritoneal macrophages in vitro and in vivo, which confirms the anti-inflammatory role of activin A (1).…”