Serum Thymic Factor Research Articles

Sex peculiarities of age-related changes in circannual rhythms of pineal gland, hypothalamo-pituitary-adrenal axis, and thymus in healthy subjects

The interrelations of circannual rhythms of the functional states of pineal gland, hypothalamo-pituitary-adrenal axis, and thymus in healthy 20–79-year-old men and women were studied. Fluctuations of melatonin, ACTH, cortisol, and serum thymic factor that are characteristic of young 20–29-year-old people changed with aging (changes of amplitudes of seasonal peaks of hormones, shift of the seasonal acrophase, monotony). Rhythmicity disorder of studied organs in men was observed earlier than in women (pineal gland and ACTH of hypophysis after 30; thymus and adrenal cortex after 40) and more prominent. The age-specific desynchronosis of melatonin production in the pineal gland is an important pathogenetic part in disturbance of rhythmicity of hypothalamo-pituitary-adrenal system and thymus.

The thymus and adaptive changes in the cellular composition of bone marrow in animals of different ages

This article studies the influence of the removal of the thymus or the administration of its biologically active factor (Thymalin) on a number of stromal precursor cells for colonies of fibroblasts (CFC-F cells), progenitor cells for granulocyte-macrophage colonies (CFC-GM cells), and CD4+ cells in bone marrow in CBA mice of different ages in different seasons of the year. It is established that in adult mice, changes of the thymus function by the number of these cell types depend on the season. This shows the possibility of a direct effect of a thymic stroma supernatant containing thymic serum factor (FTS) and synthetic FTS on the number of CFC-F and CFC-GM cells in the bone marrow of adult mice in different seasons; in old animals thymic supernatant increased the number of CD4+ cells in vitro. Administration of Thymalin to old mice led to an increase of the titer of FTS in the blood, the restoration of disturbed circannual rhythm, the number of CD4+ cells in the bone marrow, and the concentration of corticosterone in the blood.

Effect of epithalamin on the rhythm of immune and endocrine systems functioning in patients with chronic coronary disease

In contrast to young people, changes in the rhythms of parameters manifested in elderly and senile chronic coronary patients in inversion (decreased T cell count in the peripheral blood, values of lymphocyte blastogenesis test with phytohemagglutinin, and phagocytic index in the fall), monotony (B cell count in the peripheral blood), decreased amplitude of serum hydrocortisone, and desynchronization. The levels of thymic serum factor and IgG were higher in the fall than in the spring, but the seasonal difference leveled after 2.5 years of observation. On the other hand, the rhythms of changes in the thymic serum factor and hydrocortisone were retained in patients with chronic coronary disease after 6 courses of epithalamin by the optimal protocol (period of observation 30 months) and blood T cell count increased in the fall. Improvement of the rhythms of the parameters was associated with a benign clinical course of the disease.

In vivo treatment with a nonapeptide thymic hormone, facteur thymique serique (FTS), ameliorates chronic colitis induced by dextran sulphate sodium in mice

Facteur thymique serique (FTS), a thymic hormone with nonapeptide is involved in T cell differentiation in intestine. Here we investigated the effect of FTS on dextran sulphate sodium (DSS)-induced colitis. BALB/c mice were subcutaneously treated with 1 μg/mouse/day of FTS daily. FTS did not affect the course of acute colitis induced by DSS as assessed by survival rate, clinical activity of diseases, extent of tissue damage of colons. On the other hand, FTS significantly ameliorated chronic colitis induced by multiple cycles of DSS as reflected by lower lethality, weight loss, clinical scores and histological scores. The levels of interferon (IFN)-γ, interleukin 1(IL-1)-β, and IL-12p40 in the culture supernatants of lamina propria (LP) cells of colon without any stimulation and IFN-γ by T cells in the LP T cells under T cell receptor (TCR) triggering were reduced in FTS-treated mice, whereas the levels of IL-10 by LP cells and LPT cells were higher in FTS-treated mice. Thus, FTS may serve to suppress inflammation in DSS-induced chronic colitis accompanied by increased IL-10 production.

Serum thymic factor, FTS, attenuates cisplatin nephrotoxicity by suppressing cisplatin-induced ERK activation

Serum thymic factor (FTS), a thymic peptide hormone, has been reported to attenuate the bleomycin-induced pulmonary injury and also experimental pancreatitis and diabetes. In the present study, we investigated the effect of FTS on cis-diamminedichloroplatinum II (cisplatin)-induced nephrotoxicity. We have already demonstrated that cephaloridine, a nephrotoxic antibiotic, leads to extracellular signal-regulated protein kinase (ERK) activation in the rat kidney, which probably contributes to cephaloridine-induced renal dysfunction. The aim of this study was to examine the effect of cisplatin on ERK activation in the rat kidney and also the effect of FTS on cisplatin-induced nephrotoxicity in rats. In vitro treatment of LLC-PK 1 cells with FTS significantly ameliorated cisplatin-induced cell injury. Treatment of rats with intravenous cisplatin for 3 days markedly induced renal dysfunction and increased platinum contents in the kidney cortex. An increase in pERK was detected in the nuclear fraction prepared from the rat kidney cortex from days 1 to 3 after injection of cisplatin. FTS suppressed cisplatin-induced renal dysfunction and ERK activation in the kidney. FTS did not influence any Pt contents in the kidney after cisplatin administration. FTS has been shown to enhance the in vivo expression of heat shock protein (HSP) 70 in the kidney cortex. The beneficial role of FTS against cisplatin nephrotoxicity may be mediated in part by HSP70, as suggested by its up-regulation in the kidney cortex treated with FTS alone. Our results suggest that FTS participates in protection from cisplatin-induced nephrotoxicity by suppressing ERK activation caused by cisplatin.

Thymulin: An Emerging Anti-Inflammatory Molecule

Thymulin is a neuroendocrine hormone with immunoregulatory actions. Originally known as 'serum thymic factor' (FTS), thymulin binds to a carrier protein and zinc (Zn2+) to exert its biologic properties. Thymulin, albeit an es- sential hormone for the T lymphocyte differentiation and the normalization of the ratio of T-helper cells to suppressor cells, accumulating evidence suggests its involvement in inflammations of various etiologies. Recently, thymulin has been shown to have anti-nociceptive effects in hyperalgesia and in pain of neurogenic origin, ostensibly through action on sen- sory afferents and the release of anti-inflammatory mediators. Given its anti-inflammatory potential, thymulin downregu- lates the release of inflammatory mediators, such as cytokines and chemokines, upregulates anti-inflammatory factors, such as interleukin (IL)-10, and exerts molecular control via the regulation of transcription factors and mediators. Recent evidence tends to indicate that thymulin can be a therapeutic agent in many inflammatory diseases and in pathological conditions affecting the peripheral and/or the central nervous system. This review discusses current concepts in the anti- inflammatory actions of thymulin and correlates this activity with an emerging theme for therapeutic treatment.

Antigen-Induced Changes in the Endocrine Function of the Thymus in CBA Mice during Aging: Role of Peptide Factors Released by the Pineal Gland

The titer of thymic serum factor was measured in adult and old CBA females 15, 30, and 60 min, 24, 48, 72, and 96 h after injection of 3% suspension of sheep erythrocytes and changes of this parameter under the effect of epithalamin were studied in old immunized mice. The titer of thymic serum factor increased appreciably in adult mice virtually at all periods of the study after immunization (a drop was observed only 72 h after immunization). In old mice the titer of thymic serum factor virtually did not change after injection of sheep erythrocytes, while immunization of old mice preinjected with epithalamin significantly increased this parameter. Not only the values, but their dynamics in old mice injected with epithalamin corresponded to those in immunized adult animals.

Protective Effect of Serum Thymic Factor, FTS, on Cephaloridine-Induced Nephrotoxicity in Rats

Serum thymic factor (FTS), a thymic peptide hormone, has been reported to increase superoxide disumutase (SOD) levels in senescence-accelerated mice. In the present study, we examined the effect of FTS on cephaloridine (CER)-induced nephrotoxicity in vivo and in vitro. We previously reported that CER led to extracellular signal-regulated protein kinase (ERK) activation in the rat kidney. So, we also investigated whether FTS has an effect on ERK activation induced by CER. Treatment of male Sprague-Dawley rats with intravenous CER (1.2 g/kg) for 24 h markedly increased BUN and plasma creatinine levels and urinary excretion of glucose and protein, decreased creatinine clearance and also led to marked pathological changes in the proximal tubules, as revealed by electron micrographs. An increase in phosphorylated ERK (pERK) was detected in the nuclear fraction prepared from the rat kidney cortex 24 h after CER injection. Pretreatment of rats with FTS (50 microg/kg, i.v.) attenuated the CER-induced renal dysfunction and pathological damage. FTS also suppressed CER-induced ERK activation in the kidney. In vitro treatment of the established cell line, LLC-PK1 cells, with FTS significantly ameliorated CER-induced cell injury, as measured by lactate dehydrogenase (LDH) leakage. Our results, taken together with our previous report that MEK inhibitors ameliorated CER-induced renal cell injury and ERK activation induced by CER, suggest that FTS participates in protection from CER-induced nephrotoxicity by suppressing ERK activation induced by CER.

Splenic capping in the treatment of severe spleen injuries

Permanent and lifelong threat of developing fatal sepsis and other severe infections in splenectomized patients is an important reason for promoting splenic preservation. Experimental preservation of severe spleen injuries (grade IV), with splenic-capping, was performed in 30 dogs, operated using Ketalar anesthesia. Spleen preservation and concomitant treatment of excessive hemorrhage were achieved by highly controlled "conic" compression of injuried spleen parenchyma, additional hemostatic Z-sutures and fibrin tissue adhesion. Satisfactory hemostasis and complete preservation of the spleen parenchyma damage were achieved in 20% by splenic capping splenorraphy, alone. Additional placement of hemostatic sutures was necessary in 30%, and concomitant application of serum thymic factor (STF) FTA (along with sutures) in 50% of patients. The above mentioned techniques were very effective in achieving hemostasis (100%), with no mortality and low rate of postoperative complications--6.7% (1 intrasplenic abscess and 1 adhesive ileus). Excellent results and efficacy, splenic capping-splenorraphy is the method of choice in the treatment of severe and multiple transcapsular spleen injuries with involvement of segmental vessels.

Serum thymic factor prevents LPS-induced pancreatic cell damage in mice via up-regulation of Bcl-2 expression in pancreas.

The protective effect of synthetic serum thymic factor (FTS) nonapeptide on lipopolysaccharide (LPS)-induced pancreatic cell damage in 10-week-old BALB/c male mice was investigated. Mice were divided into three groups. Group I was treated with LPS (10 micro g/head; i.p.) (LPS-treated mice). Group II was administered with FTS (50 micro g/head; i.p.) 24 hr before treatment with LPS and complemented immediately before LPS injection with FTS (50 micro g/head; i.p.) (FTS-administered mice). Group III was only treated with the same volume of saline (control mice). Treatment of LPS in vivo resulted in the destruction of pancreatic acinar cells. In those cells, many apoptotic cells were detected by immunohistochemistry using an anti-single stranded DNA antibody. Immunohistochemistry and reverse transcription-polymerase chain reaction (RT-PCR) revealed that LPS treatment also caused low or a lack of insulin expression in pancreatic islets. In contrast, morphological change was not seen and apoptotic cell death was suppressed in pancreatic cells of FTS-administered mice. Moreover, insulin expression was normal in those mice. FTS administration enhanced expression of Bcl-2 mRNA levels in pancreatic tissues and IL-6 mRNA levels in splenocytes significantly compared with those of LPS treatment at 3 hr after LPS injection. These findings suggest that FTS prevents LPS-induced cell damage via enhancing Bcl-2 expression in the pancreas and systemic IL-6 production.

Effects of bioactive factors of the pineal gland on thymus function and cell composition of the bone marrow and spleen in mice of different age.

The effects of factors from the pineal gland on the titer of thymic serum factor in the supernatant of 3-h thymus stroma cultures, number of stromal precursor fibroblasts and CD4+ cells in the bone marrow, and CD8+ cells in the spleens of adult and old CBA mice were studied in vitro. Epithalamin, Epithalon, and melatonin appreciably increased the titer of thymic serum factor in the supernatant of thymus stroma cultures from mice of different age and increased the percentage of CD4+ cells in the bone marrow suspension from old animals in vitro. The percentage of CD8+ lymphocytes decreased after incubation of splenic cells from old mice with melatonin. The percentage of bone marrow fibroblast precursor cells from adult and old mice did not appreciably change after incubation with the preparations.

Effect of epithalamin on circadian relationship between the endocrine function of the thymus and melatonin-producing function of the pineal gland in elderly people.

The effect of epithalamin on circadian rhythms of thymic serum factor titers and melatonin concentrations in the blood of elderly people was studied. Course treatment with epithalamin modulated the rhythm of the thymic endocrine function. The increase in the titer of thymic serum factor at night coincided with the increase in blood melatonin concentration and shift of its acrophase to 3.00, which was characteristic of young people. In elderly people with preserved nocturnal peak of the thymic serum factor titer before therapy the nocturnal (3.00) concentration of melatonin was high and did not change after drug therapy. The correlation between melatonin concentration and titer of thymic serum factor increased after epithalamin treatment.

Suppressor mechanism of serum thymic factor on tumor necrosis factor-α-induced apoptosis in the mouse pancreatic β-cell line

Tumor necrosis factor-α (TNF-α) is a cytokine considered to play a key role in β-cell destruction in insulin-dependent diabetes mellitus (IDDM). Serum thymic factor (Facteur thymique serique; FTS) is a nonapeptide thymus hormone known to inhibit IDDM in a mouse model. In this study, the effect of TNF-α on the murine pancreatic β-cell line MIN6 was examined. Cell shrinkage and detachment were seen in cells treated with 0–50 ng/ml TNF-α for 12 h. Oligonucleosomal DNA fragmentation was determined from non-adherent cells, indicating that the TNF-α-induced cell destruction was attributed to apoptosis. Fragmented DNA was quantified by enzyme-linked immunosorbent assay to measure the amount of histone-bound oligonucleosomes. FTS was treated with TNF-α and the percentage of fragmented DNA was analyzed. The data indicate a distinct reduction of fragmented DNA at a concentration of 1 ng/ml FTS. Expression of TNF receptor I, inducible form of nitric oxide synthase (iNOS), interleukin-1β-converting enzyme (ICE), Bcl-2, and nuclear factor κB (NF-κB) was analyzed by reverse transcriptase-polymerase chain reaction to investigate the suppressor mechanism of FTS on TNF-α-induced apoptosis. FTS treatment suppressed the expression of iNOS and Bcl-2 mRNA in TNF-α-treated cells. The expression of NF-κB mRNA in TNF-α-treated cells was enhanced after FTS treatment, while that of ICE mRNA did not change in TNF-α-treated cells with or without FTS treatment. These results suggest that the inhibition of MIN6 cell death by FTS on TNF-α-induced apoptosis is caused by a negative feedback mechanism involving the inhibition of iNOS induction.

FTS reduces bleomycin-induced cytokine and chemokine production and inhibits pulmonary fibrosis in mice.

Bleomycin (BLM), an antitumour drug, is known to cause interstitial pneumonia followed by pulmonary fibrosis, and has often been used to produce an animal model of pulmonary fibrosis. In the present study, we examined the effect of a nonapeptide thymic hormone, facteur thymique serique (FTS), on the murine lung fibrosis induced by intratracheal instillation of BLM. Treatment with FTS ameliorated BLM-induced fibrotic changes in a dose-dependent manner, as indicated by the reduced accumulation of hydroxyproline (HP). In addition, FTS suppressed BLM-induced cellular inflammatory response in the lungs, as evidenced by inhibition of increased lung weight, reduced accumulation of inflammatory leucocytes, including lymphocytes and neutrophils, but not macrophages, and less pronounced histopathological changes. Finally, BLM challenge increased the local synthesis of proinflammatory cytokines, TNF-alpha and IL-1beta and chemokines, MCP-1, MIP-1alpha RANTES, MIP-2 and KC, while administration of FTS suppressed the production of these cytokines, except for MCP-1. These effects of FTS were observed only when mice received intratracheal instillation with BLM. Considered collectively, our results indicated that FTS treatment ameliorated the cellular inflammatory responses and fibrotic changes in the lungs caused by BLM and such inhibition was well correlated with reduced synthesis of several fibrosis-related cytokines, and suggested that FTS may be potentially useful for the treatment of pulmonary fibrosis.

Effects of thymic hormone on reactive oxygen species-scavengers and renal function in tacrolimus-induced nephrotoxicity

The effects of a thymic hormone (Facteur thymique serique; FTS) on renal reactive oxygen species-scavenging enzymes or substances in heminephrectomized rats with and without tacrolimus-induced nephrotoxicity were studied. Rats received both oral dose of tacrolimus (5 mg/kg/day) and subcutaneous administration of three dosages of FTS (5, 50, and 250 μg/kg/day) over 28 days (Group A). In Group B, they received three dosages of FTS alone (0.5, 5, and 50 μg/kg/day) or FTS 50 μg/kg/day with tacrolimus over 28 days. Each dose of FTS (Group A) partially elevated renal creatinine clearances. Tacrolimus enhanced renal glutathione reductase (GSH-R) activities and glutathione (GSH) and depressed catalase (CAT) activities. FTS increased GSH levels and GSH-R activities. Although FTS alone did not change CAT activities, CAT activities recovered as a result of concomitant use of FTS (Groups A and B). A significant positive correlation was found between CAT activity and creatinine clearance. These findings suggest that FTS is useful for the prevention of tacrolimus-induced nephrotoxicity, and that the increase of renal CAT activity in the defense mechanism of FTS might be important for cell protection against active oxygen species.

A thymic hormone protects mice from enteropathy during acute graft-versus-host disease.

We have previously reported that a nonapeptide thymic hormone, facteur thymique serique (FTS), is involved in the differentiation and activation of intestinal intraepithelial lymphocytes (i-IEL) in mice. In this study, we examined the effect of FTS treatment on enteropathy in a murine model for acute graft-vs.-host disease (GVHD) induced by injection of parental C57BL/6 splenocytes into unirradiated (C57BL/6 x DBA/2) F1 hybrids. FTS treatment significantly protected mice from developing acute GVHD as assessed by mortality rate, splenomegaly and enteropathy. The infiltration of donor-derived TCR alpha beta i-IEL bearing CD8 alpha beta was significantly inhibited in the small intestine of FTS-treated mice, and the frequencies of apoptosis of crypt cells in the intestinal mucosa were decreased in these mice during acute GVHD. These results suggest that FTS treatment contributes to protection against enteropathy of acute GVHD. Thus, FTS may provide a useful approach to control acute GVHD after blood transfusion or bone marrow transplantation.

Effects of a Nonapeptide Thymic Hormone on Intestinal Intraepithelial Lymphocytes in Mice Following Administration of 5-Fluorouracil

A significant fraction of murine small intestinal intraepithelial lymphocytes (i-IELs) maturate in local sites outside the thymus. However, there is evidence suggesting that extrathymic differentiation of i-IELs is still influenced by the thymus or thymus-derived factors. Facteur thymique serique (FTS), a nonapeptide thymic hormone, is involved in several aspects of intra- and extrathymic T cell differentiationin vivo.In this study, we investigated the effects of FTS on the kinetics of i-IELs in mice following a single administration of 5-fluorouracil (5-FU). FTS treatment significantly accelerated the recovery in cell number of i-IELs after administration of 5-FU. Flow cytometric analysis revealed that this accelerated recovery was mainly due to a rapid increase in CD8αα+i-IELs. Similar findings were also evident in adult thymectomized (ATX) mice, indicating that FTS treatment caused a rapid recovery of CD8αα+i-IELs following 5-FU administration in the absence of a functional thymus. Furthermore, expression levels of the mRNAs for interleukin-2, interferon-γ, and transforming growth factor β1in the i-IELs were augmented by FTS treatment. Notably, FTS treatment protected mice from 5-FU-induced lethal toxicity, accompanied with an inhibition of the translocation ofEnterobactericeae.These results suggest that FTS has an important function in the extrathymic maturation and activation of i-IELs in the small intestine following 5-FU administration, which may contribute at least partly to the protection against 5-FU-induced lethal toxicity.

Activation of canine monocytes and polymorphonuclear cells by serum thymic factor (FTS) in vivo.

The effect of serum thymic factor (FTS) was evaluated from the immunoresponse augmented in canine monocytes and polymorphonuclear cells (PMN) using the chemiluminescence technique. FTS did not affect the number of leukocytes and differential count of leukocytes. CL activity of the whole blood was significantly elevated by FTS from 72 hr to 120 hr after administration (p < 0.05), and that at 96 hr after administration was about 3-fold higher than that before the administration. The CL response of PMN was significantly elevated by FTS administration from 24 hr to 96 hr after administration (p < 0.05), and that at 48 hr after administration was about 7-fold higher than prior treatment. FTS also significantly elevated the CL response of monocyte from 24 hr to 96 hr after administration (p < 0.01), and the CL count of monocyte in 24 hr and 48 hr was about 100-fold higher than that before FTS administration. These findings suggested that FTS may be efficacious and useful immuno-potentiator for canine monocytes and PMN.

In vivo administration of serum thymic factor (FTS) prevents EMC-D virus-induced diabetes and myocarditis in BALB/cAJcl mice.

The effect of serum thymic factor (FTS) on the D-variant of encephalomyocarditis (EMC-D) virus-induced diabetes and myocarditis in BALB/cAJcl mice was investigated. Mice pretreated with 50 or 10 micrograms of FTS were infected with 10 or 10(3) PFU of EMC-D virus. In the mice inoculated with 10 PFU of virus, 40% developed diabetes on post-infection day (PID) 14, whereas those treated with FTS (50 micrograms/administration) on day 2 and 1 before infection did not develop diabetes. FTS (10 micrograms)-pretreated mice developed diabetes. In histological observation, FTS non-treated mice which developed diabetes showed severe necrosis and inflammation of mononuclear cells in the islets of Langerhans and myocardia on 19 PID. Mice pretreated with 50 micrograms of FTS, however, manifested mild islet degeneration without any myocardial inflammation. Furthermore, in FTS non-treated mice, immunohistological staining showed a loss of insulin granules. This loss was markedly reversed and insulin granules remained largely intact in FTS-pretreated mice. Viral titers in pancreas of FTS-pretreated mice approximated well to those of non-treated mice on PID 4, 7 and 19. In mice inoculated with higher titer of EMC-D virus (10(3) PFU), however, 50 micrograms of FTS pretreatment did not change the course of these acute pathological developments (diabetes and myocarditis observed from PID 4).

Effect of administration of serum thymic factor (FTS) in calves and rabbits infected with bovine immunodeficiency-like virus.

The effect of serum thymic factor (FTS) administration in bovine immunodeficiency-like virus (BIV)-infected calves and rabbits was examined. We previously found that some of the macrophage functions were depressed and humoral immune responses against foreign proteins were delayed in BIV-infected calves compared to uninfected calves. After FTS administration, however, no delay of antibody responses against foreign proteins was observed in BIV-infected calves. Though the chemiluminescence (CL) responses of macrophages in BIV-infected calves were significantly depressed (p < 0.05), FTS administration resulted in the recovery of the CL responses in the BIV-infected calves comparable to those in the control calves. Antibody responses against foreign proteins in BIV-infected rabbits were significantly depressed (p < 0.025) as compared with those in uninfected rabbits, though the depression became no significant after FTS administration.