Thymosin β 4 sulfoxide is an anti-inflammatory agent generated by monocytes in the presence of glucocorticoids

Abstract

The possibility that glucocorticoids upregulate the expression of anti-inflammatory mediators is an exciting prospect for therapy in inflammatory diseases, because these molecules could give the therapeutic benefits of steroids without toxic side effects. Supernatants from monocytes and macrophages cultured in the presence of glucocorticoids increase the dispersion of neutrophils from a cell pellet in the capillary tube migration assay. This supernatant factor, unlike other neutrophil agonists, promotes dispersive locomotion of neutrophils at uniform concentration, lowers their adhesion to endothelial cells, inhibits their chemotactic response to fMLP and induces distinctive morphological changes. Here we show that thymosin beta4 sulfoxide is generated by monocytes in the presence of glucocorticoids and acts as a signal to inhibit an inflammatory response. In vitro, thymosin beta4 sulfoxide inhibited neutrophil chemotaxis, and in vivo, the oxidized peptide, but not the native form, was a potent inhibitor of carrageenin-induced edema in the mouse paw. Thymosin beta4 is unique, because oxidation attenuates its intracellular G-actin sequestering activity, but greatly enhances its extracellular signaling properties. This description of methionine oxidation conferring extracellular function on a cytosolic protein may have far-reaching implications for future strategies of anti-inflammatory therapy.

Ku80 as a Novel Receptor for Thymosin β4 That Mediates Its Intracellular Activity Different from G-actin Sequestering

“…Although it is a typical intracellular polypeptide, it plays numerous roles, both intracellularly and extracellularly. Numerous observations indicate that T␤4 is involved in adhesion and spreading of fibroblasts (1, 2), differentiation of endothelial cells (3, 4), directional migration of endothelial cells and keratinocytes (5-8), angiogenesis (3-6, 9, 10), wound healing (6, 7, 11), hair follicle growth (8), and apoptosis (12, 13), and has been described to possess anti-inflammatory properties (11,14). In addition, elevated T␤4 expression has been observed in various malignant cell lines and tumors (15-17) and its levels seem to be associated with increased tumorigenicity and metastatic potential (10, 13, 18 -20).…”

Formation and Implications of a Ternary Complex of Profilin, Thymosin β4, and Actin

“…De La Cruz et al (13) have recently investigated the thermodynamics of the interaction between thymosin ␤ 4 and actin, and report evidence that the conformational transition may also involve changes in actin conformation. The molecular interactions of unfolded proteins, such as thymosin ␤ 4 , with ligand have been proposed by Wright and Dyson (20) to provide regulatory control over critical cellular functions, and indeed, in addition to its actinbinding properties, thymosin ␤ 4 exhibits complex biological activities related to immunosuppression and hematopoesis (21)(22)(23). Presumably these diverse signaling pathways require multiple binding partners, a situation made possible by the potential of thymosin ␤ 4 to adopt induced structural motifs selective and specific for diverse ligands.…”

Selective glucocorticoid receptor agonists (SEGRAs): Novel ligands with an improved therapeutic index

“…Similarly, there are genes that negatively regulate the immune system that are positively regulated by the GR. For example, thymosin β4 sulfoxide (Young et al, 1999), glucocorticoid-induced leucine zipper (GILZ) (Berrebi et al, 2003), macrophage migration inhibitory factor (MIF) (Calandra et al, 1995), lipocortin-1 (Mizuno et al, 1997) and MKP-1 (Kassel et al, 2001) are some of the known genes that negatively regulate processes in the immune system but are transcriptionally upregulated by GCs. Thus the transactivation / transrepression model for the screening of anti-inflammatory glucocorticoids with reduced side effects, although attractive, has some limitations.…”