Medical Hypotheses Medico/Hypotheses (1993) 41.470-472 0 Longman Gmup UK Ltcl 1993

Thymus-Neuroendocrine-Liver Pathway

L. LI*t, J.H. ZHOU*, ST. XING* and B.H.S. LAUt

*Institute of Pharmacology and Toxicology, Beijing 100850, China, t Depatiment of Microbiology, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA (Reprint requests to BHSL)

Abstract-In order to investigate the influence of the thymus on liver functions, we used adult thymectomized rats as a model and supplemented the animals with either thymic extracts or sex hormones. Male thymectomized rats exhibited a decrease in liver microsomal cytochrome P-450 and aminopyrine-N-demethylase activities. There was also a decrease in the levels of hypothalamic luteinizing hormone-releasing hormone (LHRH), plasma luteinizing hormone (LH) and testosterone. Supplementation of testosterone propionate to these animals restored their liver P-450 and demethylase activities to normal levels. Female thymectomized rats showed an increase of liver malondialdehyde (MDA), accompanied by a decrease of liver superoxide dismutase (SOD) and glutathione (GSH), and a decline of fluidity and calcium ion uptake in liver microsomal and mitochondrial membranes. There was also a decline in hypothalamic LHRH and plasma estradiol. Supplementation of thymic extract to female thymectomized rats decreased the liver MDA, increased the liver GSH, and restored the microsomal and mitochondrial membrane fluidity and calcium ion uptake. The decrease of liver MDA was also achieved by administration of estradiol benzoate. The data suggest that the thymus may influence liver functions through the hypothalamus-pituitary-gonad axis. Thus, a new ‘thymus-neuroendocrine-liver pathway’ is proposed that further affirms the significance of the thymus on maintaining homeostasis and integrative functions in the body.

Introduction

Experimental and clinical investigations over the past 3 decades have led to a recognition of the thymus as the master gland of immunity. These investiga- tions have also provided evidence that the thymus is an important endocrine organ. During the 1980s there was an emergence of literature relating the in- teractions between the thymus and the neurodocrine system. Rebar et al (1) reported that congenitally athymic nude mice had a reduced pituitary con-

centration of luteinizing hormone (LH) and follicle- stimulating hormone (FSH). These hormones could be restored to normal levels by thymic transplanta- tion on the first day of life. They also found that partially purified thymosin fraction 5 and one of its synthetic peptide components, thymosin p4, stimu- lated the secretion of luteinizing hormone-releasing hormone (LHRH) from superfused medial basal hy- pothalami of female rats (2). Healy et al (3) docu- mented that thymectomy of juvenile macaques was associated with the decrease of plasma cortisol, corti-

Date received 8 May 1992 Date accepted 10 July 1992

470

THYMUS-NEUROENDOCRINE-LIVER PATHWAY 471

cotropin and P-endorphin, which was reversed when thymosin fraction 5 was administered intravenously to prepubertial cynomolgus monkeys. Geenan et al (4) reported that the neuropeptides oxytocin (OT) and va- sopressin (VP) were synthesized in the human thymus in a similar manner as in the hypothalamic-neuro- hypophyseal system. They also reported that thymic OT and VP might play an active role in T cell differ- entiation and activation (4). The data suggest that the interactions between the thymus and neuroendocrine system are reciprocal, thus constituting a complicated thymus-neuroendocrine network (5, 6).

In 1988 Hao et al (7) reported the increase of mal- ondialdehyde (MDA, a metabolite of lipid peroxida- tion) in the liver of female adult thymectomized mice with no increase of MDA in the brain. It is well kno,wn that the liver is the largest and most active organ for metabolism and detoxification. The thymus is an immune organ according to the traditional con- cept, and there appears to be no interactions between the ,thymus and the liver. Since we now recognize that the thymus plays an important role in neuroendocrine- immune network, we hypothesize that the thymus may also influence the liver through the neuroen- docrine system. During the past 2 years, we have in- vestigated the influence of the thymus on liver func- tions and its intermediary pathways and have obtained experimental data to support our hypothesis that there is a ‘thymus-neuroendocrine-liver pathway’.

The injkence of the thymus on liver functions

We used adult thymectomized Wistar rats as a mo’del and observed the changes of liver microsomal drug-metabolizing enzymes, lipid peroxidation and biomembrane functions in these animals. We found that their liver microsomal cytochrome P-450 content and aminopyrine-N-demethylase activity continued to decline at 4, 6 and 8 months after thymectomy and the decrease was more obvious in the male than in the female rats (8).

On the other hand, the liver homogenate and mi- crosomal MDA content increased at 6 and 8 months after thymectomy in the female, but not in the male rats. The increase in MDA was accompanied by a decrease in liver glutathione (GSH) and superoxide dismutase (SOD) (9, 10). Thymectomy also produced a rnarked decrease in fluidity and calcium ion uptake of liver microsomal and mitochondrial membranes in the female rats (11).

Supplementation of thymic factor D (polypeptides extracted from swine thymus) to the female thymec- tomized rats decreased the liver MDA, increased the liver GSH, and elevated the liver microsomal and mi-

tochondrial membrane fluidity and calcium ion uptake

(11).

Intermediary pathway by which the thymus injkences the [iver

Since sex differences were exhibited in the above ex- periments, we speculated that sex hormones might act as mediators between the thymus and the liver. Therefore, the second part of our study focused on the effects of sex hormones on liver functions. It was found that hypothalamic LHRH and plasma LH declined at 2 and 3 months after thymectomy of male rats, followed by a decrease of plasma testos- terone at 4, 6 and 8 months. Subcutaneous injection of androgen (testosterone propionate) restored their decreased liver cytochrome P-450 and aminopyrine- N-demethylase activities (8). In female rats, the hy- pothalamic LHRH and plasma estradiol decreased at 6 months after thymectomy (12). The administration of estrogen (estradiol benzoate) reversed the increase of liver MDA (13).

In order to further confirm that sex hormones exert an influence on the liver, we observed the changes of liver functions in rats after removal of gonads. We found that liver drug-metabolizing enzyme ac- tivity decreased in adult castrated rats. This decrease was more significant in the male than in the female, which was a mirror image of the changes observed in the thymectomized rats. Supplementation of testos- terone propionate to male castrated rats restored the enzyme activity to normal levels, while administra- tion of estradiol benzoate to the female castrated rats did not show any significant effects (8).

On the other hand, the increase in liver MDA was more significant in the female castrated rats than in the castrated males, which was consistent with the changes observed in the thymectomized rats. Injec- tion of estrogen caused the liver MDA to decrease in female castrated rats, while the injection of androgen did not have any effect in the castrated males (13).

Conclusion

The data from our studies demonstrate that the thy- mus plays an important role in maintaining the drug- metabolizing enzyme activity, anti-oxidative ability and biomembrane integrity in the liver of rats. These effects are mediated by sex hormones. The thy- mus exerts a significant influence on circulating sex hormones through the hypothalamus-pituitary-gonad axis. These sex hormones in turn act as intermediary factors in regulating liver functions. Androgen mainly mediates the regulation of the thymus on liver drug- metabolizing enzymes in male rats, while estrogen

472 MEDICAL HYPOTHESES

mainly mediates the effect of the thymus on liver anti-oxidative functions in female rats. On the basis of these findings, a new ‘thymus-neuroendocrine-liver pathway’ is proposed (Fig.).

Hypothalamus

1

LHRH

Pituitary

i

LH, FSH

Gonad

1 THYMUS

I Sex hormones

Androgen Estrdgen

LXVER LIVER

drug-metabolizing enzyme anti-oxidative timction

Fig. Thymus-neuroendocrine-liver pathway.

Thus, we believe that the thymus not only plays an important role in immunity, but also influences circu- lating hormonal levels (such as sex hormones) by reg- ulating the neuroendocrine system. These hormones may further act on the corresponding target organs (such as liver) and produce more extensive effects on different systems, thus maintaining homeostasis and integrative functions in the body.

Acknowledgements

Lin Li is a recipient of a research fellowship supported by the Chan Shun Research Fund for AIDS and Cancer (Chan Shun Interna- tional Foundation, Burlingame, CA).

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