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. 2003 May;109(1):1-7.
doi: 10.1046/j.1365-2567.2003.01616.x.

Anti-inflammatory effects in the skin of thymosin-beta4 splice-variants

Michael Girardi  1 , Michael A Sherling, Renata B Filler, John Shires, Efstathios Theodoridis, Adrian C Hayday, Robert E Tigelaar
Affiliations

Anti-inflammatory effects in the skin of thymosin-beta4 splice-variants

Michael Girardi et al. Immunology. 2003 May.

Abstract

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.

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Figures

Figure 1
Figure 1
Differential expression of LTβ4 in activated DETCs. Autoradiogram of gel electrophoresed showing 32P-labelled products, sampled at 18, 20, 22, 24, 26 and 28 cycles, covering a linear range pre-established by pilot experiments. The products were generated using primers specific for LTβ4, UTβ4 and β-actin, as indicated. As determined by densitometry, LTβ4 is expressed at higher levels in activated DETCs than in resting DETCs, while the expression of UTβ4 is similar in resting and activated DETCs.
Figure 2
Figure 2
λ-Carrageenan induced inflammation, representative of neutrophil-mediated inflammation. Micrometer-measured increases in footpad swelling in mice injected with λ-carrageenan intradermally into the footpad, and treated with PBS; UTβ4 or its methionated derivative; LTβ4 or its methionated derivative. (a) At 24 hr, mice that received LTβ4 had a significantly reduced footpad swelling than mice receiving either PBS or UTβ4. (b) At both 6 hr and 24 hr mice that received mlTβ4 had a significantly reduced footpad swelling than mice receiving either PBS or mUTβ4.
Figure 3
Figure 3
TPA irritant contact dermatitis assay. Micrometer-measured increases in ear thickness in naive mice in which ICD was elicited by application of TPA, and that were treated with PBS; methionated UTβ4; or methionated LTβ4. The mlTβ4 suppressed TPA-induced ear swelling significantly more than PBS at 6 hr and 24 hr, and significantly more than mUTβ4 at 6 hr.
Figure 4
Figure 4
DNFB allergic contact dermatitis assay. ACD was elicited in mice previously sensitized on abdominal skin with DNFB by epicutaneous challenge of the ear skin with low-dose DNFB. Micrometer-measured increases in ear thickness mice treated with PBS; UTβ4 or its methionated derivative; or LTβ4 or its methionated derivative. (a) At 6 hr, 24 hr, and 72 hr after challenge, mice that received LTβ4 demonstrated a significant reduction in ear swelling response when compared to mice receiving PBS or UTβ4. There was no significant suppression of ACD by UTβ4. (b) mlTβ4 showed a significant reduction in ear swelling response at 24 hr and 72 hr relative to mice that received PBS or mUTβ4.
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