Thymosin Beta 4 Promotes Corneal Wound Healing and Modulates Inflammatory Mediators in vivo

Sosne, Gabriel; Chan, Chi Chao; Thai, Khoan; Kennedy, Michael; Szliter, Elizabeth A.; Hazlett, Linda D.; Kleinman, Hynda K.

doi:10.1006/exer.2000.0985

Cited by 148 publications

(161 citation statements)

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“…It has been demonstrated that elevated expression of EGF, a mitogen acting on endothelial cells among others, augments angiogenesis and enhances metastasis formation in melanoma. 71 T␤4 has a potent chemotactic properties for endothelial cells, 72 and its expression was associated with increased vascularization of B16(F10) tumors. 63 Likewise, overexpression of HYAL1 and MCT1 resulted in higher microvessel density in bladder cancer 64 and breast cancer, 73 respectively.…”

Section: Discussionmentioning

confidence: 99%

Overexpression of Heme Oxygenase-1 in Murine Melanoma

Waś

Cichoń²,

Smolarczyk³

et al. 2006

The American Journal of Pathology

174

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Heme oxygenases (HOs) catalyze the oxidation of heme to the biologically active products carbon monoxide (CO), biliverdin, and ferrous iron. Two distinct variants of HOs have been described in humans and rodents, each encoded by a different gene: HO-2, which is constitutively expressed, and HO-1, which is potently induced in many cell types by heme, inflammatory cytokines, and oxidative stress-related factors.

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Section: Discussionmentioning

confidence: 99%

Overexpression of Heme Oxygenase-1 in Murine Melanoma

Waś

Cichoń²,

Smolarczyk³

et al. 2006

The American Journal of Pathology

174

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“…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)(6)(7)(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)(16)(17) and its levels seem to be associated with increased tumorigenicity and metastatic potential (10, 13, 18 -20).…”

mentioning

confidence: 99%

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

Bednarek

Boncela

Smolarczyk

et al. 2008

Journal of Biological Chemistry

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Our data demonstrate that increased intracellular expression of thymosin ␤4 (T␤4) is necessary and sufficient to induce plasminogen activator inhibitor type 1 (PAI-1) gene expression in endothelial cells. To describe the mechanism of this effect, we produced T␤4 mutants with impaired functional motifs and tested their intracellular location and activity. Cytoplasmic distributions of T␤4 (AcSDKPT/4A) , T␤4 (KLKKTET/7A) , and T␤4 (K16A) mutants fused with green fluorescent protein did not differ significantly from those of wild-type T␤4. Overexpression of T␤4, T␤4 (AcSDKPT/4A) , and T␤4 (K16A) affected intracellular formation of actin filaments. As expected, T␤4 (K16A) uptake by nuclei was impaired. On the other hand, overexpression of T␤4 (KLKKTET/7A) resulted in developing the actin filament network typical of adhering cells, indicating that the mutant lacked the actin binding site. The mechanism by which intracellular T␤4 induced the PAI-1 gene did not depend upon the N-terminal tetrapeptide AcSDKP and depended only partially on its ability to bind G-actin or enter the nucleus. Both T␤4 and T␤4 (AcSDKPT/4A) induced the PAI-1 gene to the same extent, whereas mutants T␤4 (KLKKTET/7A) and T␤4 (K16A) retained about 60% of the original activity. By proteomic analysis, the Ku80 subunit of ATPdependent DNA helicase II was found to be associated with T␤4. Ku80 and T␤4 consistently co-immunoprecipitated in a complex from endothelial cells. Co-transfection of endothelial cells with the Ku80 deletion mutants and T␤4 showed that the C-terminal arm domain of Ku80 is directly involved in this interaction. Furthermore, down-regulation of Ku80 by specific short interference RNA resulted in dramatic reduction in PAI-1 expression at the level of both mRNA and protein synthesis. These data suggest that Ku80 functions as a novel receptor for T␤4 and mediates its intracellular activity.2 is the most abundant member of the highly conserved family of acidic polypeptides called ␤-thymosins. 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). The increased expression of T␤4 correlates with the invasive capability of the cells, the degree of morphologic transformation, and disintegration of actin filaments (21). Recent studies have also correlated increased T␤4 expression with potentiated cell growth (13, 22) but this observation seems not to be universal (2, 10).T␤4 is conside...

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“…Passive immunization with anti-MIP-1␣ Ab inhibited the development of arthritis in anti-type II collagen Ab-induced arthritis and delayed the onset and reduced the severity of CIA (38,40). Decreased levels of the MIP-1␣ mRNA transcript were reported in mice treated with thymic peptides (41). In this study, we showed that AdProT⌬NLS downregulated the MIP-1␣ promoter activity induced by TNF-␣ in rat synovial fibroblasts, resulting in lower levels of MIP-1␣, IL-1␤, and TNF-␣, as well as decreased macrophage infiltration in the ankle joints of rats with CIA.…”

Section: Figurementioning

confidence: 96%

Prothymosin α Lacking the Nuclear Localization Signal as an Effective Gene Therapeutic Strategy in Collagen-Induced Arthritis

Shiau¹,

Chen²,

Chang³

et al. 2007

The Journal of Immunology

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Prothymosin α (ProT) is regulated by c-Myc, an oncoprotein overexpressed in synovium of rheumatoid arthritis, and is associated with cell proliferation. However, ProT also exerts immunomodulatory activities. The growth-promoting activity of ProT can be abolished by deleting its nuclear localization signal (NLS). In this study, we showed that AdProTΔNLS, an adenoviral vector encoding ProT lacking the NLS, did not enhance the proliferation of synovial fibroblasts. AdProTΔNLS treatment abolished the up-regulation of the MIP-1α promoter activity induced by TNF-α in synovial fibroblasts. AdProTΔNLS suppressed macrophage chemotaxis and reduced macrophage infiltration into the ankle joints in rats with collagen-induced arthritis (CIA). Neutralization test confirmed the involvement of MIP-1α in macrophage chemotaxis. Administration of AdProTΔNLS reduced the severity of CIA in the clinical, radiographic, and histological aspects. The levels of TNF-α (mean ± SEM, 1261.9 ± 107.9 vs 2880.1 ± 561.4 pg/mg total protein; p < 0.05), IL-1β (56.8 ± 8.0 vs 109.2 ± 4.9 pg/mg total protein; p < 0.01), and MIP-1α (41.7 ± 3.6 vs 55.2 ± 1.1 pg/mg total protein; p < 0.05) in the ankle joints were lower in the AdProTΔNLS-treated rats with CIA than those in their control counterparts. In the AdProTΔNLS-treated ankle joints, matrix metalloproteinase-9 expression was decreased by 40% and infiltrating macrophages reduced by 50%. Our results demonstrate that intra-articular delivery of AdProTΔNLS significantly ameliorated the clinical course of CIA in rats. This study is the first to suggest that ProT lacking the NLS may have therapeutic potential for the management of rheumatoid arthritis.

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Thymosin Beta 4 Promotes Corneal Wound Healing and Modulates Inflammatory Mediators in vivo

Cited by 148 publications

References 50 publications

Overexpression of Heme Oxygenase-1 in Murine Melanoma

Overexpression of Heme Oxygenase-1 in Murine Melanoma

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

Prothymosin α Lacking the Nuclear Localization Signal as an Effective Gene Therapeutic Strategy in Collagen-Induced Arthritis

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