- Email: [email protected]
The inhibitory effect of hydrocortisone on interferon production by rat spleen cells
0022-4731/89 $3.00 + 0.00 Pergamon Press plc
J. sreroid &&hem. Vol. 33, No. 6, pp. 1139-l 141, 1989 Printed in Great Britain
THE INHIBITORY EFFECT OF HYDROCORTISONE ON INTERFERON PRODUCTION BY RAT SPLEEN CELLS DING JIAYI, YANG SHIKUN’and Xv RENBAO* Department of Pathophysiology
and ‘Immunology, Second Military Medical College,
Shanghai 200433, China (Received 4 October 1988; received for publication 6 July 1989)
Summary-The effect of hydrocortisone on interferon r(IFN-r) production by rat spleen cells and its mechanism were studied. The results showed that hydrocortisone inhibited IFN-r production at concentrations as low as 5.52 x lo-i0 M, with complete suppression at 5.52 x lo-* M, and the total number and survival rate of the cultured spleen cells were not apparently affected by 5.52 x 1Om8M hydrocortisone. The inhibitory effect was dosedependent when the concentration was from 5.52 x lo-lo M to 5.52 x lo-* M and could be blocked by RU38486, a competitive antagonist of glucocorticoid. Our results suggested that glucocorticoid may inhibit IFN-r production through a receptor-mediated mechanism.
INTRODUCTION
The study of immunomodulation by glucocorticoids has come to a new era since the discovery of inhibitory effect of dexamethasone on interleukin 2(IL-2) production at low concentrations [l]. Afterwards, it was found that many lymphokines, such as interleukin l(IL-I), macrophage activating factor (MAF) and Fc receptor augmenting factor (FRAF), were inhibited by glucocorticoids at low concentrations [2-4] and the functions of T lymphocytes and natural killer (NK) cells suppressed by glucocorticoids as well [5,6]. Interferon r(IFN-r), one of the lymphokines secreted by activated T lymphocyte, plays an important role in immunomodulation besides its antiviral action, especially in the regulation of the functions of NK cells and macrophages. Recently, it was reported that some lymphokines inhibited by glucocorticoids, such as MAF and FRAF, were actually IFN-r [7,8], and IFN-r production by cloned T lymphoma cells might be inhibited by glucocorticoids [9]. But whether IFN-r production by normal lymphocytes was inhibited by glucocorticoids still remains unsettled. In this study, the effect of hydrocortisone on IFN-r production in rat spleen cells and its mechanism were studied. EXPERIMENTAL Animals and reagents
Sprague-Dawley rats weighing 180-250 g were obtained from the Animal Laboratory of the Second Military Medical College. RPM11640 was purchased from Nissui Pharmaceutical (Japan). For spleen cell culture, serum-free RPM11640 medium (RPM11640 *Author to whom all correspondence should he addressed.
supplemented with 0.25% human serum albumin, 4% amino acid solution, 5 x 10e6 M 2-mercaptoethanol, penicillin (100 IU/ml) and streptomycin (100 pg/ml)) was used. Pokewood Mitogen (PWM) was purchased from Boehringer Mannheim (Germany), hydrocortisone provided by Sine Pharmaceutical (China) and RU38486 kindly provided by Roussel-Uclaf (France). Cell culture and IFN-r production
Spleen was removed from the rat adrenalectomized 72 h previously. Cells were separated by gently pressing the spleen with a glass rod within a steel network (200 pores/cm*) immersed in the culture medium. After being centrifuged at 1000 rpm for 10 min, the cells were resuspended in the culture medium to a density of approximately 10’ cells/ml for IFN-r production. PWM was added to the suspension to the final concentration of 10 pg/ml. The viability of the cells was examined by exclusion of trypan blue. The effect of hydrocortisone on IFN-r production and blocking effect of RU38486 on hydrocortisone
Hydrocortisone was added to the spleen suspension to the final concentrations as indicated in Fig. 1. After the cells were incubated in 5% CO, for 72 h, the supematant was collected for measurement of IFN-r. To block the action of hydrocortisone, RU38486 was added together with hydrocortisone to the final concentrations as indicated in Fig. 2. Measurement of IFN-r
IFN-r was quantified by measuring its ability to protect murine L929 cell line from infection by vesicular stomatitis virus (VSV) using a modified microcytopathic effect inhibitory assay [lo]. Briefly, 8 x lo-’ L929 cells were cultured for 24 h in the
1139
1140
DING JIAY~ et al.
presence of serial dilutions of a IFN-r sample in a total volume of 200~1 per well in the microplate. The resulting L929 cell monolayers were washed and then challenged by VSV. The microplate was read when the control wells showed a complete cytopathic effect of the virus. Titer of IFN, which provided 50% protection of the cells from the cytopathic effect of the virus, was defined as the maximal dilution of the IFN-r sample. The reciprocal of titer was defined as the units per ml of IFN-r. RESULTS
Eflect of hydrocortisone on the viability of spleen cells
As it was reported that glucocorticoids may cause cytolysis of lymphocytes in rodents [I I], the effect of hydroco~isone on the lability and number of spleen ceils was observed in this study. After the cells were incubated with 5.52 x lo-* M hydrocortisone for 72 h , its viability and number were not different from that of the control group (Table 1). When the concentration increased to 5.52 x 10m6M, however, the cell number decreased as compared to that of the control (data not shown). Thus, in subsequent experiments, the final con~ntrations of hydrocortisone were controlled below 5.52 x lo-‘M. EfSect of hydrocortisone on IFN-r production
Using PWM as the inducer, the titer of IFN produced by rat spleen cells was between 1:320 to 1640. This IFN was unstable to heat (56°C 30 min) and low pH (pH 2, 4°C for 24 h), suggesting it was mainly IFN-r. The IFN-r production was suppressed by hydrocortisone at the concentration as low as 5.52 x lo-‘* M, and completely inhibited by 5.52 x lo-’ M hydrocortisone. The inhibitory effect of hydrocortisone was dose-dependent within this range (Fig. 1). The blocking effect of RU38486 on hydrocortisone
When the spleen cells were cultured in the presence of 5.52 x 10s8 M hydroco~isone and 10 pg/ml PWM, no IFN-r could be detected in the supematant, if 10m6M RU38486 was added, however, IFN-r titer was reversed to the level of the control group. The Table 1. Effect of hydrocortisone of rat
spleen
Animal No.
1 2 3 4 5
Control Survival Number ( x 104) rate (“%) 53 54 54 48 60
I100 XrtSE
1360.2f97.8
53.8+
0.55
1.1
1.7
2.2 2.76
Hydrocortisone
13.8
(nM)
Fig. I. Effect of hydrocortisone on IFN-r production. 1 x lO’/ml rat spleen cells were cultured in the presence of lOl,cg/ml PWM and hydrocortisone at the final concentrations as indicated. Supematant was collected for IFN-r assay 72 h later. Values are mean f SE of 6 experiments.
effect of RU38486 was also dose-de~ndent from 10e9 M to 10e6 M, and RU38486 itself had no effect on IFN-r production (Fig. 2). DISCUSSION
The concentration of free glucocorticoid in rat fluctuates from 5.52 x 10s9 M to 5.52 x lo-’ M diurnally. Our results showed hydr~ortisone inhibited IFN-r production within the range from 5.52 x lo-iOM to 5.52 x lo-* M. The spleen cells were obtained from the adrenalectomized rat, which eliminated the effect of endogenous glucocorticoid on IFN-r production. The use of serum-free culture medium removed the possible actions of exogenous glucocorticoids and other hormones from animal serum. Though hydrocortisone is the main natural glucoco~icoid in man and other higher mammalian (not in rat), its binding affinity to glucocorticoid receptors and biological potencies were similar to that of corticosterone, the main natural glucocorticoid in rat and other rodents [12]. Thus, it is reasoanble to conclude that glucocorticoid at the concentrations within physiological range may inhibit IFN-r production. It has been reported that many immunolo~cal functions and the production of lymphokines might
on the number and survival rate
cells. The cells were incubated with 55.2 x IO-* M hvdrocortisone for 72 h
1328 1424 I392 I664 2080 1136 1168 1100 1210
fOOr
1.9
or without
5.52 nM hydr~ortisoae Survival Number (x IO”) rate f%) 1312 1360 1360 1856 2080 1104 1200 toso 1150 12io 1368.2t106.5
60 54 54 48 58
54.8*2.1
mM~” RU36488
0 (Ml
0
0 10-B
55.2 0
55.2 10-S
55.2 10-a
55.2 10-7
55.2 10-s
Fig. 2. The effect of RU38486 on the action of hydrocortisone. 1 x lO’/ml rat spleen cells were cultured in the presence of lOpg/ml PWM, with various concentrations of RU38486 as indicated and 55.2nM hydrocortisone. Supematant was taken for IFN-r assay 72 h later. Values are means f SE of 6 experiments. F: hydrocortisone.
Inhibition of interferon by hydrocortisone be inhibited by glucocorticoids at low concentrations. The view that glucocorticoid in oiuo may regulate the immune functions has also been accepted. But whether this effect of glucocorticoids, like its other physiological functions, is receptor-mediated has not yet been clarified. Our results showed that the dose-response curve of hydrocortisone on IFN-r production and the concentration-binding curve of [3H]dexamethasone to rat spleen cells were very similar (unpublished data), indicating that the inhibition of IFN-r production by hydrocortisone was receptormediated. Our results further proved that 10e6M RU38486 completely blocked the inhibitory action of 5.52 x lo-’ M hydrocortisone on IFN-r production. A dose-dependent blocking effect of RU38486 was also demonstrated when it ranged from 10m9M to 10m6M. The blocking curve of RU38486 on the action of hydrocortisone parallelled with the displacement curve of the binding of [3H]dexamethasone by Ru38486 in rat spleen cells (data not shown). RU38486 is a synthetic competitive antagonist of glucocorticoids, it has the same binding sites per cell as dexamethasone and can block many effects of glucocorticoids, either in uiuo or in vitro [13]. Thus, it might be concluded that glucocorticoids inhibited IFN-r production by a receptor-mediated mechanism. The interaction between the neuroendocrine and immune system has been one of the most actively studied areas in biological sciences during the past 10 yr. It has been found that many hormones secreted by the neuroendocrine system may affect the immune function [14,15]. Some cytokines produced by the immune system were also proved to provoke neuroendocrine activities [16, 171. A bidirectional circuit between the two systems was proposed as well [18, 191. The significances of the circuit were believed to protect the body from harmful effects of immune reactions [20]. As IFN-r strongly enhances the functions of NK cell and macrophage during the immune responses [21,22], it may be suggested that inhibition of IFN-r by glucocorticoid might protect the body from the overproliferative effects of the immune responses. Acknowledgement-We
thank Zheng Linli of the Department of Immunology of our college for technical assistance.
1141
4. Kelso A., Glasebrook A. L., Kanagawa 0. and Brunner K. T.: Production of macrophage-activating factor by T lymphocyte clones and correlation with other lymphokine activities. J. Immun. 129 (1982) 550-556. 5. Schleimer R. P., Jacques A., Shin H. S., Lichtenstein L. M. and Plaut M.: Inhibition of T cell-mediated cytotoxicity by anti-inflammatory steroids. J. Immun. 132 (1984) 266271. 6. Holbrook N. J., Cox W. M. and Horner H. C.: Direct suppression of natural killer activity in human peripheral blood leukocyte cultures by glucocorticoids and its modulation by interferon. Cancer Rex 43 (1983) 40194025. 7. Scheiber R. D., Pace J. L., Russell S. W., Altman A. and Katz D. H.: Macrophage-activating factor produced by a T cell hybridoma: physiochemical and biosynthetic resemblance to r-interferon. J. Immun. 131 (1983) 82-32. 8. Guyre P. M., Morganelli P. M. and Miller R.: Recombinant immune interferon increases immunoglobulin G Fc receptors on cultured human mononuclear phagocytes. J. Clin. Invest. 72 (1983) 393-397. 9. Kelso A. and Munck A.: Glucocorticoid inhibition of lymphokine secretion by alloreactive T lymphocyte clones. J. Immun. 133 (1984) 784-791. IO. Epstein L. B.: Assay of human immune interferon from lymphocyte macrophage cultures by a virus plague reduction method. In Manual of Clinical Immunology (Edited by Rose N. R. and Herman F.). American Society for Microbiology, Washington, D.C. (1976). 11. Claman H. N.: Corticosteroids and lymphoid cells. New Engl. J. Med. 287 (1972) 388-397.
12. Munck A. and Kiu L.: Glucocorticoid receptors and mechanisms of action. In Receptor and Mechanism of Action of Steroid Hormones, Part II (Edited by Pasqualini J. R.). Dekker, New York (1977). 13. Phlibert D.: RU38486: An original multifaceted antihormone in vivo. In Adrenal Steroid Antagonism. de Gruyter, Berlin (1984). 14. Cupps T. R. and Fauci A. S.: Corticosteroid-mediated immunoregulation in man. Immun. Rev. 65 (1982) 132-155.
15. Coffey R. G. and Djeu A. J.: Endocrine receptors on lymphocytes: Integration of endocrine and immune systems. In The Recepiors (Edited by Conn P. M.). Academic Press, New York, Vol IV (1986). 16. Besedovsky H. O., Rey A. D., Sorkin E. and Dinarello C. A.: Immunoregulatory feedback between interleukin-1 and glucocorticoid hormones. Science (1986) 652-654. 17. Sapolsky R., Rivier C., Yamamoto G., Plotsky P. and Vale W.: Interleukin-1 stimulates the secretion of hypothalamic corticotropin-releasing factor. Science 238 (1987) 522-524.
D. and Smith 18. Blalock J. E., Harbour-Mcmenamin E. M.: Peptide hormones shared by the neuroendocrine and immunological systems. J. Immun. 135 (1985) 858~461s.
REFERENCES
Gillis S., Crabtree G. R. and Smith K. A.: Glucorticoidinduced inhibition of T cell growth factor productionI. The effect on mitogenlinduced lymphocyte proliferation. J. Immun. 123 (19791 1624-1631. Guyre P. M., Bodwell J. E: and’Munck A.: Glucocorticoid actions on the immune system: Inhibition of production of an Fc-receptor augmenting factor. J. Steroid Eiochem. 15 (1981) 35-39. Snyder D. S. and Unanue E. R.: Corticoids inhibit murine macrophage Ia expression and interleukin 1 production. J. Immun. 129 (1982) 1803-1805.
19. Weigant D. and Blalock J. E.: Interaction between the neuroendocrine and immune systems: Common hormones and recenters. Immun. Rev. 100 (1987) . , 79-107. 20. Besedovsky H. O., Rey D. A. and Sorkin E.: Immuneneuroendocrine interactions. J. Immun. 135 (1985) 75os-754s.
21. Epstein L. B.: Interferon-gamma: Is it really different from the other interferon? In Interferon (Edited by Gresser I.). Academic Press, New Y&k, Voi. 3 (19811. 22. Hamilton T. A. and Adams D. 0.: Molecular mechanisms of signal transduction in macrophages. Immun. Today 8 (1987) 151-158.
J. sreroid &&hem. Vol. 33, No. 6, pp. 1139-l 141, 1989 Printed in Great Britain
THE INHIBITORY EFFECT OF HYDROCORTISONE ON INTERFERON PRODUCTION BY RAT SPLEEN CELLS DING JIAYI, YANG SHIKUN’and Xv RENBAO* Department of Pathophysiology
and ‘Immunology, Second Military Medical College,
Shanghai 200433, China (Received 4 October 1988; received for publication 6 July 1989)
Summary-The effect of hydrocortisone on interferon r(IFN-r) production by rat spleen cells and its mechanism were studied. The results showed that hydrocortisone inhibited IFN-r production at concentrations as low as 5.52 x lo-i0 M, with complete suppression at 5.52 x lo-* M, and the total number and survival rate of the cultured spleen cells were not apparently affected by 5.52 x 1Om8M hydrocortisone. The inhibitory effect was dosedependent when the concentration was from 5.52 x lo-lo M to 5.52 x lo-* M and could be blocked by RU38486, a competitive antagonist of glucocorticoid. Our results suggested that glucocorticoid may inhibit IFN-r production through a receptor-mediated mechanism.
INTRODUCTION
The study of immunomodulation by glucocorticoids has come to a new era since the discovery of inhibitory effect of dexamethasone on interleukin 2(IL-2) production at low concentrations [l]. Afterwards, it was found that many lymphokines, such as interleukin l(IL-I), macrophage activating factor (MAF) and Fc receptor augmenting factor (FRAF), were inhibited by glucocorticoids at low concentrations [2-4] and the functions of T lymphocytes and natural killer (NK) cells suppressed by glucocorticoids as well [5,6]. Interferon r(IFN-r), one of the lymphokines secreted by activated T lymphocyte, plays an important role in immunomodulation besides its antiviral action, especially in the regulation of the functions of NK cells and macrophages. Recently, it was reported that some lymphokines inhibited by glucocorticoids, such as MAF and FRAF, were actually IFN-r [7,8], and IFN-r production by cloned T lymphoma cells might be inhibited by glucocorticoids [9]. But whether IFN-r production by normal lymphocytes was inhibited by glucocorticoids still remains unsettled. In this study, the effect of hydrocortisone on IFN-r production in rat spleen cells and its mechanism were studied. EXPERIMENTAL Animals and reagents
Sprague-Dawley rats weighing 180-250 g were obtained from the Animal Laboratory of the Second Military Medical College. RPM11640 was purchased from Nissui Pharmaceutical (Japan). For spleen cell culture, serum-free RPM11640 medium (RPM11640 *Author to whom all correspondence should he addressed.
supplemented with 0.25% human serum albumin, 4% amino acid solution, 5 x 10e6 M 2-mercaptoethanol, penicillin (100 IU/ml) and streptomycin (100 pg/ml)) was used. Pokewood Mitogen (PWM) was purchased from Boehringer Mannheim (Germany), hydrocortisone provided by Sine Pharmaceutical (China) and RU38486 kindly provided by Roussel-Uclaf (France). Cell culture and IFN-r production
Spleen was removed from the rat adrenalectomized 72 h previously. Cells were separated by gently pressing the spleen with a glass rod within a steel network (200 pores/cm*) immersed in the culture medium. After being centrifuged at 1000 rpm for 10 min, the cells were resuspended in the culture medium to a density of approximately 10’ cells/ml for IFN-r production. PWM was added to the suspension to the final concentration of 10 pg/ml. The viability of the cells was examined by exclusion of trypan blue. The effect of hydrocortisone on IFN-r production and blocking effect of RU38486 on hydrocortisone
Hydrocortisone was added to the spleen suspension to the final concentrations as indicated in Fig. 1. After the cells were incubated in 5% CO, for 72 h, the supematant was collected for measurement of IFN-r. To block the action of hydrocortisone, RU38486 was added together with hydrocortisone to the final concentrations as indicated in Fig. 2. Measurement of IFN-r
IFN-r was quantified by measuring its ability to protect murine L929 cell line from infection by vesicular stomatitis virus (VSV) using a modified microcytopathic effect inhibitory assay [lo]. Briefly, 8 x lo-’ L929 cells were cultured for 24 h in the
1139
1140
DING JIAY~ et al.
presence of serial dilutions of a IFN-r sample in a total volume of 200~1 per well in the microplate. The resulting L929 cell monolayers were washed and then challenged by VSV. The microplate was read when the control wells showed a complete cytopathic effect of the virus. Titer of IFN, which provided 50% protection of the cells from the cytopathic effect of the virus, was defined as the maximal dilution of the IFN-r sample. The reciprocal of titer was defined as the units per ml of IFN-r. RESULTS
Eflect of hydrocortisone on the viability of spleen cells
As it was reported that glucocorticoids may cause cytolysis of lymphocytes in rodents [I I], the effect of hydroco~isone on the lability and number of spleen ceils was observed in this study. After the cells were incubated with 5.52 x lo-* M hydrocortisone for 72 h , its viability and number were not different from that of the control group (Table 1). When the concentration increased to 5.52 x 10m6M, however, the cell number decreased as compared to that of the control (data not shown). Thus, in subsequent experiments, the final con~ntrations of hydrocortisone were controlled below 5.52 x lo-‘M. EfSect of hydrocortisone on IFN-r production
Using PWM as the inducer, the titer of IFN produced by rat spleen cells was between 1:320 to 1640. This IFN was unstable to heat (56°C 30 min) and low pH (pH 2, 4°C for 24 h), suggesting it was mainly IFN-r. The IFN-r production was suppressed by hydrocortisone at the concentration as low as 5.52 x lo-‘* M, and completely inhibited by 5.52 x lo-’ M hydrocortisone. The inhibitory effect of hydrocortisone was dose-dependent within this range (Fig. 1). The blocking effect of RU38486 on hydrocortisone
When the spleen cells were cultured in the presence of 5.52 x 10s8 M hydroco~isone and 10 pg/ml PWM, no IFN-r could be detected in the supematant, if 10m6M RU38486 was added, however, IFN-r titer was reversed to the level of the control group. The Table 1. Effect of hydrocortisone of rat
spleen
Animal No.
1 2 3 4 5
Control Survival Number ( x 104) rate (“%) 53 54 54 48 60
I100 XrtSE
1360.2f97.8
53.8+
0.55
1.1
1.7
2.2 2.76
Hydrocortisone
13.8
(nM)
Fig. I. Effect of hydrocortisone on IFN-r production. 1 x lO’/ml rat spleen cells were cultured in the presence of lOl,cg/ml PWM and hydrocortisone at the final concentrations as indicated. Supematant was collected for IFN-r assay 72 h later. Values are mean f SE of 6 experiments.
effect of RU38486 was also dose-de~ndent from 10e9 M to 10e6 M, and RU38486 itself had no effect on IFN-r production (Fig. 2). DISCUSSION
The concentration of free glucocorticoid in rat fluctuates from 5.52 x 10s9 M to 5.52 x lo-’ M diurnally. Our results showed hydr~ortisone inhibited IFN-r production within the range from 5.52 x lo-iOM to 5.52 x lo-* M. The spleen cells were obtained from the adrenalectomized rat, which eliminated the effect of endogenous glucocorticoid on IFN-r production. The use of serum-free culture medium removed the possible actions of exogenous glucocorticoids and other hormones from animal serum. Though hydrocortisone is the main natural glucoco~icoid in man and other higher mammalian (not in rat), its binding affinity to glucocorticoid receptors and biological potencies were similar to that of corticosterone, the main natural glucocorticoid in rat and other rodents [12]. Thus, it is reasoanble to conclude that glucocorticoid at the concentrations within physiological range may inhibit IFN-r production. It has been reported that many immunolo~cal functions and the production of lymphokines might
on the number and survival rate
cells. The cells were incubated with 55.2 x IO-* M hvdrocortisone for 72 h
1328 1424 I392 I664 2080 1136 1168 1100 1210
fOOr
1.9
or without
5.52 nM hydr~ortisoae Survival Number (x IO”) rate f%) 1312 1360 1360 1856 2080 1104 1200 toso 1150 12io 1368.2t106.5
60 54 54 48 58
54.8*2.1
mM~” RU36488
0 (Ml
0
0 10-B
55.2 0
55.2 10-S
55.2 10-a
55.2 10-7
55.2 10-s
Fig. 2. The effect of RU38486 on the action of hydrocortisone. 1 x lO’/ml rat spleen cells were cultured in the presence of lOpg/ml PWM, with various concentrations of RU38486 as indicated and 55.2nM hydrocortisone. Supematant was taken for IFN-r assay 72 h later. Values are means f SE of 6 experiments. F: hydrocortisone.
Inhibition of interferon by hydrocortisone be inhibited by glucocorticoids at low concentrations. The view that glucocorticoid in oiuo may regulate the immune functions has also been accepted. But whether this effect of glucocorticoids, like its other physiological functions, is receptor-mediated has not yet been clarified. Our results showed that the dose-response curve of hydrocortisone on IFN-r production and the concentration-binding curve of [3H]dexamethasone to rat spleen cells were very similar (unpublished data), indicating that the inhibition of IFN-r production by hydrocortisone was receptormediated. Our results further proved that 10e6M RU38486 completely blocked the inhibitory action of 5.52 x lo-’ M hydrocortisone on IFN-r production. A dose-dependent blocking effect of RU38486 was also demonstrated when it ranged from 10m9M to 10m6M. The blocking curve of RU38486 on the action of hydrocortisone parallelled with the displacement curve of the binding of [3H]dexamethasone by Ru38486 in rat spleen cells (data not shown). RU38486 is a synthetic competitive antagonist of glucocorticoids, it has the same binding sites per cell as dexamethasone and can block many effects of glucocorticoids, either in uiuo or in vitro [13]. Thus, it might be concluded that glucocorticoids inhibited IFN-r production by a receptor-mediated mechanism. The interaction between the neuroendocrine and immune system has been one of the most actively studied areas in biological sciences during the past 10 yr. It has been found that many hormones secreted by the neuroendocrine system may affect the immune function [14,15]. Some cytokines produced by the immune system were also proved to provoke neuroendocrine activities [16, 171. A bidirectional circuit between the two systems was proposed as well [18, 191. The significances of the circuit were believed to protect the body from harmful effects of immune reactions [20]. As IFN-r strongly enhances the functions of NK cell and macrophage during the immune responses [21,22], it may be suggested that inhibition of IFN-r by glucocorticoid might protect the body from the overproliferative effects of the immune responses. Acknowledgement-We
thank Zheng Linli of the Department of Immunology of our college for technical assistance.
1141
4. Kelso A., Glasebrook A. L., Kanagawa 0. and Brunner K. T.: Production of macrophage-activating factor by T lymphocyte clones and correlation with other lymphokine activities. J. Immun. 129 (1982) 550-556. 5. Schleimer R. P., Jacques A., Shin H. S., Lichtenstein L. M. and Plaut M.: Inhibition of T cell-mediated cytotoxicity by anti-inflammatory steroids. J. Immun. 132 (1984) 266271. 6. Holbrook N. J., Cox W. M. and Horner H. C.: Direct suppression of natural killer activity in human peripheral blood leukocyte cultures by glucocorticoids and its modulation by interferon. Cancer Rex 43 (1983) 40194025. 7. Scheiber R. D., Pace J. L., Russell S. W., Altman A. and Katz D. H.: Macrophage-activating factor produced by a T cell hybridoma: physiochemical and biosynthetic resemblance to r-interferon. J. Immun. 131 (1983) 82-32. 8. Guyre P. M., Morganelli P. M. and Miller R.: Recombinant immune interferon increases immunoglobulin G Fc receptors on cultured human mononuclear phagocytes. J. Clin. Invest. 72 (1983) 393-397. 9. Kelso A. and Munck A.: Glucocorticoid inhibition of lymphokine secretion by alloreactive T lymphocyte clones. J. Immun. 133 (1984) 784-791. IO. Epstein L. B.: Assay of human immune interferon from lymphocyte macrophage cultures by a virus plague reduction method. In Manual of Clinical Immunology (Edited by Rose N. R. and Herman F.). American Society for Microbiology, Washington, D.C. (1976). 11. Claman H. N.: Corticosteroids and lymphoid cells. New Engl. J. Med. 287 (1972) 388-397.
12. Munck A. and Kiu L.: Glucocorticoid receptors and mechanisms of action. In Receptor and Mechanism of Action of Steroid Hormones, Part II (Edited by Pasqualini J. R.). Dekker, New York (1977). 13. Phlibert D.: RU38486: An original multifaceted antihormone in vivo. In Adrenal Steroid Antagonism. de Gruyter, Berlin (1984). 14. Cupps T. R. and Fauci A. S.: Corticosteroid-mediated immunoregulation in man. Immun. Rev. 65 (1982) 132-155.
15. Coffey R. G. and Djeu A. J.: Endocrine receptors on lymphocytes: Integration of endocrine and immune systems. In The Recepiors (Edited by Conn P. M.). Academic Press, New York, Vol IV (1986). 16. Besedovsky H. O., Rey A. D., Sorkin E. and Dinarello C. A.: Immunoregulatory feedback between interleukin-1 and glucocorticoid hormones. Science (1986) 652-654. 17. Sapolsky R., Rivier C., Yamamoto G., Plotsky P. and Vale W.: Interleukin-1 stimulates the secretion of hypothalamic corticotropin-releasing factor. Science 238 (1987) 522-524.
D. and Smith 18. Blalock J. E., Harbour-Mcmenamin E. M.: Peptide hormones shared by the neuroendocrine and immunological systems. J. Immun. 135 (1985) 858~461s.
REFERENCES
Gillis S., Crabtree G. R. and Smith K. A.: Glucorticoidinduced inhibition of T cell growth factor productionI. The effect on mitogenlinduced lymphocyte proliferation. J. Immun. 123 (19791 1624-1631. Guyre P. M., Bodwell J. E: and’Munck A.: Glucocorticoid actions on the immune system: Inhibition of production of an Fc-receptor augmenting factor. J. Steroid Eiochem. 15 (1981) 35-39. Snyder D. S. and Unanue E. R.: Corticoids inhibit murine macrophage Ia expression and interleukin 1 production. J. Immun. 129 (1982) 1803-1805.
19. Weigant D. and Blalock J. E.: Interaction between the neuroendocrine and immune systems: Common hormones and recenters. Immun. Rev. 100 (1987) . , 79-107. 20. Besedovsky H. O., Rey D. A. and Sorkin E.: Immuneneuroendocrine interactions. J. Immun. 135 (1985) 75os-754s.
21. Epstein L. B.: Interferon-gamma: Is it really different from the other interferon? In Interferon (Edited by Gresser I.). Academic Press, New Y&k, Voi. 3 (19811. 22. Hamilton T. A. and Adams D. 0.: Molecular mechanisms of signal transduction in macrophages. Immun. Today 8 (1987) 151-158.