Thymosin β4 reduces lethality and down-regulates inflammatory mediators in endotoxin-induced septic shock

Badamchian, Mahnaz; Fágárásan, Mirela O.; Danner, Robert L.; Suffredini, Anthony F.; Damavandy, Hadi; Goldstein, Allan L.

doi:10.1016/s1567-5769(03)00024-9

Cited by 97 publications

(88 citation statements)

References 24 publications

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“…Therefore, intervention in NF-κB activation can eliminate the induced overexpression of proinflammatory cytokines such as TNF-α, IL-1β and IL-6. As reviewed recently, thymosin β4 has clear anti-inflammatory and anti-septic shock activities (12,26). In addition, thymosin β4 can inhibit TNF-α-mediated NF-κB nuclear translocation and activation (15,16,27).…”

Section: Discussionmentioning

confidence: 99%

“…Thymosin β4 has shown promising efficacy in animal models of various diseases, such as myocardial infarction, dermal wounds, multiple sclerosis, sepsis and endotoxic shock (12,20,(28)(29)(30)(31). However, to the best of our knowledge, there have been no reports concerning thymosin β4 in the treatment of acute pancreatitis until now.…”

Section: Discussionmentioning

confidence: 99%

“…There is growing evidence that thymosin β4 has numerous biological functions in addition to actin binding and sequestration. It has been shown to downregulate a number of key inflammatory mediators (e.g., IL-1β and TNF-α) and decreases the infiltration of inflammatory cells (11)(12)(13)(14). Thymosin β4 has also been found to reduce inflammation by inhibiting the activation of NF-κB in TNF-α-induced cells (15,16).…”

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Effects of thymosin β4 on a rat model of severe acute pancreatitis

et al. 2015

Experimental and Therapeutic Medicine

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Abstract. The aim of the present study was to investigate the effects of thymosin β4 on a rat model of severe acute pancreatitis (SAP) induced by sodium taurocholate (STC) and the underlying mechanism. SAP was induced by the retrograde infusion of 5% STC (1 ml/kg) into the bile-pancreatic duct. In certain rats, thymosin β4 (30 mg/kg) was administered intraperitoneally 30 min prior to the infusion of STC. The severity of pancreatitis was evaluated by the measurement of serum amylase, lipase, tumor necrosis factor-α, interleukin (IL)-1β, IL-6 and myeloperoxidase (MPO) levels, and histological grading. Nuclear factor (NF)-κB activation was evaluated by immunohistochemistry and western blot analysis. Intercellular adhesion molecule (ICAM)-1 protein expression in the pancreas was studied using western blot analysis. Prophylactic administration of thymosin β4 was found to attenuate serum amylase and lipase activity and the serum concentrations of proinflammatory cytokines. In addition, it attenuated pathological pancreatic injury, pancreatic MPO activity, and the activation of NF-κB and ICAM-1 in the pancreas. These results suggest that thymosin β4 exerts a protective effect against STC-induced pancreatic injury. IntroductionAcute pancreatitis is an inflammatory disease of the pancreas characterized by acute abdominal pain and increased concentrations of serum amylase and lipase. In the majority of cases, it runs a mild course without complications. However, ~25% patients develop severe acute pancreatitis (SAP), which may result in systemic inflammatory response syndrome and subsequent multiple organ dysfunction syndrome, and the mortality rate is up to 40% (1,2). In recent years, many investigators have attempted to reveal the pathogenesis of acute pancreatitis; however, the exact mechanisms are not well understood. Accumulating evidence indicates that SAP is closely associated with tissue injury and microcirculation disorders resulting from the production of proinflammatory cytokines and mediators, including tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6 and intercellular adhesion molecule (ICAM)-1 (3,4). In addition, studies have shown that acute pancreatitis can lead to activation of the nuclear factor (NF)-κB signaling pathway (5,6). Therefore, reducing the levels of proinflammatory cytokines and adhesion molecules to block the inflammatory cascade may be a valid treatment strategy for acute pancreatitis.Thymosin β4 is a highly conserved polypeptide that was originally isolated from bovine thymus gland extract in 1981 (7). Thymosin β4 contains 43-amino acid residues with a molecular weight of 4964.5 Da and an isoelectric point of 4.6 (8). It is widely distributed in many tissues and cell types and is found in high concentrations in blood platelets, macrophages and white blood cells, but not in red blood cells (9). The most prominent physiological role of thymosin β4 as the major actin-sequestering peptide contributes to the regulation of actin polymerization in mammalian nucleated cells (10). There is g...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Effects of thymosin β4 on a rat model of severe acute pancreatitis

et al. 2015

Experimental and Therapeutic Medicine

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“…Previous findings have reported that Tβ4 was involved in inflammation, but most observed anti-inflammatory effects of Tβ4. For example, Tβ4 inhibited expression of inflammatory mediators in endotoxin-induced septic shock (37). It also appeared to have an anti-inflammatory effect in neonatal rats by inhibiting microglia activation through microRNA146a (38), and it inhibited the activation of NF-κB in TNF-α-stimulated cells (39).…”

Section: Thymosin β4 and Rheumatoid Arthritismentioning

confidence: 99%

Thymosin β4 in rheumatoid arthritis: Friend or foe

Kim

Yang

2017

Biomedical Reports

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Abstract. Rheumatoid arthritis (RA) has characteristic pannus tissues, which show tumor-like growth of the synovium through chronic joint inflammation. The synovium is highly penetrated by various immune cells, and the synovial lining becomes hyperplastic due to increased numbers of macrophage-like and fibroblast-like synoviocytes. Thus, a resultant hypoxic condition stimulates the expression of inflammation-related genes in various cells, in particular, vascular endothelial growth factor. Thymosin β4 (Tβ4), a 5-kDa protein, is known to play a significant role in various biological activities, such as actin sequestering, cell motility, migration, inflammation, and damage repair. Recent studies have provided evidence that Tβ4 may have a role in RA pathogenesis. The Tβ4 level has been shown to increase significantly in the joint fluid and serum of RA patients. However, whether Tβ4 stimulates or inhibits activation of RA immune responses remains to be determined. In the present study, we discuss the logical and clinical justifications for Tβ4 as a potential target for RA therapeutics. IntroductionCytokines control an extensive range of inflammatory progressions that are associated with the pathogenesis of rheumatoid arthritis (RA). In arthritic joints, pro-inflammatory activities lead to the induction of autoimmunity, chronic inflammation, and, ultimately, joint damage (1). A better understanding of these pathogenic mechanisms has enabled the development of therapeutic agents to inhibit cytokine actions, such as tumor necrosis factor-α (TNF-α), interleukin (IL)-1, and IL-6, which have greatly contributed to the management of RA patients (2,3). Biological therapies have contributed innovative improvements to RA treatment (4). However, despite these improvements, 30-50% of RA patients who are non-responders to disease-modifying antirheumatic drugs (DMARDs) fail to respond to treatment with biologic agents (5). Furthermore, radiographic joint damage can proceed even when clinical disease reduction is achieved by biologic agents (6).These results indicate that the inhibition of cytokine networks may not be satisfactory to suppress RA progression. Thus, there is a need for new therapeutic agents to target new molecules, which encouraged us to redirect our efforts to screen other therapeutic targets from joint synovial fluids of RA patients. Recently, we observed that the level of thymosin β4 (Tβ4), which has many biological roles, was significantly increased in the serum and joint fluids of RA patients (7,8). This review aims to discuss the current understanding of the potential role of Tβ4 in RA pathogenesis while addressing current knowledge regarding the association between Tβ4 and arthritic joints for RA management. Rheumatoid arthritisRA is an autoimmune inflammatory disease whose pathogenic mechanisms remain elusive. RA pathogenesis is attributed to a complex interaction between genetic and environmental factors (7). The class II major histocompatibility complex molecules HLA-DR1 and HLA-DR4 are regarded as major...

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“…Thymosin ß4 (Tß4) is a small protein that is normally composed of 43-amino acids and is the most abundant member of the ß-thymosins, which are linked to a number of important biological actions, including actin polymerization, angiogenesis, wound healing, inflammation and signaling through the Akt pathway (23)(24)(25)(26)(27)(28)(29)(30)(31)(32). Recent studies have shown that Tß4 is frequently overexpressed in malignant tumors and increases tumor growth, metastasis and epithelial-mesenchymal transition (EMT) (33)(34)(35).…”

Section: Introductionmentioning

confidence: 99%

Thymosin β4 expression correlates with lymph node metastasis through hypoxia inducible factor-α induction in breast cancer

Cho¹

2010

Oncol Rep

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Abstract. Intratumoral hypoxia has been correlated with distant metastatic potential. Two hypoxia inducible factors (HIFs), HIF-1· and HIF-2·, are induced by hypoxia, and high expression of these proteins has been correlated to angiogenesis and distant metastasis. Thymosin ß4 (Tß4) is frequently highly expressed in cancer, and this overexpression correlates with malignant progression. The objective of this study was to investigate the clinical correlation of HIF-· with Tß4 and the intracellular functional roles of Tß4 on HIF-· activation. We examined HIF-1·, HIF-2· and Tß4 expressions in clinical human breast carcinoma (n=70) by immunohistochemistry. We show that high expression of HIF-1· and HIF-2· strongly correlates with Tß4 expression (P≤0.0001) and overexpression of Tß4 correlates significantly with patients with lymph node metastasis (P<0.05) of human breast cancer. Additionally, we demonstrate that hypoxia up-regulates intracellular Tß4 protein, which then affects HIF-· activity, which is the key in regulating VEGF expression. We confirmed that hypoxia-induced intracellular Tß4 and HIF-· activities were reduced by interference of Tß4 expression using Tß4 shRNA lentivirus. Vascular epidermal growth factor (VEGF)-A, a well-recognized lymphangiogenic cytokine, was also downregulated, but VEGF-C and VEGF-D expressions were not affected. These findings suggest that the overexpression of Tß4 is strongly associated with HIF-1· and HIF-2· expression and is also clinicopathologically involved with lymph node metastatic potential of breast cancer through the modulation of HIF-· activation and induction of VEGF-A. Ultimately, these results highlight Tß4 as a potentially therapeutic target in malignant cancers.

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Thymosin β4 reduces lethality and down-regulates inflammatory mediators in endotoxin-induced septic shock

Cited by 97 publications

References 24 publications

Effects of thymosin β4 on a rat model of severe acute pancreatitis

Effects of thymosin β4 on a rat model of severe acute pancreatitis

Thymosin β4 in rheumatoid arthritis: Friend or foe

Thymosin β4 expression correlates with lymph node metastasis through hypoxia inducible factor-α induction in breast cancer

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