Anti-inflammatory effects in the skin of thymosin-beta4 splice-variants.
The intraepithelial lymphocyte (IEL) network of T-cell receptor gammadelta+ (Vgamma5+) dendritic epidermal T cells (DETC) in murine skin down-regulates cutaneous inflammation, although the mechanism is unknown. Thymosin-beta4 (Tbeta4), identified by serial analysis of gene expression as a predominant transcript in gut IEL, encodes both a ubiquitous actin-binding protein (UTbeta4) with demonstrated capacity to inhibit neutrophilic infiltration, and a splice-variant limited to lymphoid tissue (LTbeta4) with unknown bioactivity. Freshly isolated Vgamma5+ DETCs expressed both forms, while only LTbeta4 was preferentially up-regulated after cellular activation in vitro. To compare the anti-inflammatory properties of LTbeta4 and UTbeta4 in the skin in vivo, the biological activities of synthesized polypeptides were assessed using three different strategies: neutrophil infiltration by footpad lambda-carrageenan injection; irritant contact dermatitis to 12-O-tetradecanoylphorbol 13-acetate; and allergic contact dermatitis to 2,4-dinitrofluorobenzene. These studies clearly showed that the anti-inflammatory activities of LTbeta4 were broader and most often stronger than those of UTbeta4. Thus, the activation-responsive expression of the lymph-specific form of Tbeta4 may be one mechanism by which DETC, and possibly other IELs, down-regulate local inflammation.
Girardi
Michael
M
Department of Dermatology and the Yale Skin Diseases Research Core Center, Yale University, New Haven, Connecticut 06520, USA.
Sherling
Michael A
MA
Filler
Renata B
RB
Shires
John
J
Theodoridis
Efstathios
E
Hayday
Adrian C
AC
Tigelaar
Robert E
RE
D017398:Alternative Splicing; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D001681:Biological Assay; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000378:metabolism*; D017449:Dermatitis, Allergic Contact / Q000188:drug therapy; D003877:Dermatitis, Contact / Q000188:drug therapy*; D017453:Dermatitis, Irritant / Q000188:drug therapy; D005260:Female; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use*; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000032:analysis; D012867:Skin / Q000378:metabolism; D013947:Thymosin / Q000235:genetics*; D000099201:Thymosin beta(4)
D000893:Anti-Inflammatory Agents; D008840:Microfilament Proteins; D016692:Receptors, Antigen, T-Cell, gamma-delta; D013947:Thymosin; D000099201:Thymosin beta(4)