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Interleukin-6 (IL-6) administration to human subjects or experimental animals induces changes in thyroid hormone metabolism resembling those in the sick euthyroid syndrome. Furthermore, the decrease in serum T3 during illness is significantly related to serum IL-6 concentrations. These findings suggest, but do not prove, a causal role for IL-6 in the development of the low T3 syndrome. The aim of the present study was to evaluate the role of IL-6 in the development of the sick euthyroid syndrome in IL-6 knock-out (IL-6(-/-)) mice compared to that in wild-type mice (IL-6(+/+)). Illness was induced in IL-6(-/-) and IL-6(+/+) mice by 1) administration of bacterial endotoxin (LPS), 2) infection with Listeria monocytogenes, and 3) turpentine injection in both hind limbs. Food intake was kept similar in both groups in all three experiments. Serial measurements were made of serum IL-6, tumor necrosis factor-alpha, T3, T4, corticosterone, and liver 5'-deiodinase (5'-DI) messenger RNA (mRNA) for 24 h (LPS), 96 h (L. monocytogenes), and 48 h (turpentine). Serum IL-6 increased in response to all stimuli in IL-6(+/+) mice, but not in IL-6(-/-) mice. Serum tumor necrosis factor-alpha was induced by LPS in both groups to a similar extent, but did not rise after L. monocytogenes or turpentine administration. Serum T3 and T4 decreased after all three stimuli. The decrease in serum T4 in IL-6(-/-) was similar to that in IL-6(+/+) mice. The decrease in serum T3, however, was smaller in the IL-6(-/-) mice than in the IL-6(+/+) mice; T3 levels were 1.56 +/- 0.29 and 0.99 +/- 0.15 nmol/liter, respectively, 24 h after LPS treatment (P < 0.01), 2.39 +/- 0.17 and 1.75 +/- 0.24 nmol/liter 96 h after L. monocytogenes treatment (P < 0.01), and 1.46 +/- 0.18 and 1.10 +/- 0.25 nmol/liter 48 h after turpentine treatment (P < 0.05). The smaller fall in serum T3 in IL-6(-/-) mice could not be attributed to differences in the severity of the induced illness, food intake, or corticosterone response, which were all similar in IL-6(-/-) mice and IL-6(+/+) mice. Liver 5'-deiodinase mRNA decreased after all three stimuli; the decrease after LPS and L. monocytogenes infection was smaller in the IL-6(-/-) mice, but the difference in IL-6(+/+) mice just failed to reached statistical significance. Liver 5'-deiodinase activity after turpentine injection administration decreased in the wild-type animals by 36%, but did not change in the knock-out mice. In conclusion, acutely induced illness generates the low T3 syndrome, which is less marked in IL-6 knock-out mice than in wild-type mice. The data suggest a causal role of IL-6 in the development of the low T3 syndrome.

The effects of inflamed nasal mucosa from pigs with atrophic rhinitis (AR), cell extract from Bordetella bronchiseptica, conditioned medium from Pasteurella multocida, and purified dermonecrotic toxin (DNT) from P. multocida on mouse fetal long bones in organ culture were studied. Inflamed nasal "AR mucosa" stimulated the release of 45Ca from prelabeled cultures, while histologically the formation of calcified matrix was impaired as well. B. bronchiseptica cell extract only transiently increased 45Ca release, but also impaired the formation of matrix. 45Ca release was also stimulated by DNT-containing conditioned medium from P. multocida and by purified DNT. The effect of DNT was biphasic: low doses (1 to 25 ng/ml) slightly stimulated bone resorption, higher doses were inhibitory. The stimulatory action of DNT on 45Ca release was accompanied by an increase in numbers of preosteoclasts and osteoclasts. The significance of these findings for the pathogenesis of AR is discussed.

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The pars intermedia of teleosts contains two types of granular cells with the predominant type being similar to the pars intermedia cells in other vertebrate groups and containing peptides derived from the pro-opiomelanocortin precursor molecule. The function and products of the second cell type, the PAS positive cells, are unknown. This study reports on the identification of biosynthetic products of the PAS positive cells of the cichlid teleost Sarotherodon mossambicus. The experimental regimen took advantage of earlier morphometric analyses which showed marked differences in metabolic activity of the PAS positive cells resulting from adaptation to different background colours and illumination. Autoradiography at the light microscopic level showed that both cell types of the pars intermedia incorporate labeled amino acids during/// vitro incubation. To identify the prod ucts synthesized by the PAS positive cells, labeled products of the pars intermedia tissue were analysed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and highpressure liquid chromatography. Comparison of pulse incubations of pars intermedia tissue of fish adapted to different backgrounds and conditions of illumination revealed that an increase in the number and metabolic activity of the PAS positive cells, as deduced from morphometric data, was paralleled by an increase of the amount of label incorporated into 27K and 25K molecules. Pulse-chase experiments with pars intermedia lobes of white and black background adapted fish showed that these two products, unlike the other newly synthesized products, were not involved in any precursor-product relationship. Our data, therefore, suggest that the 27K and 25K peptides were synthesized by the PAS positive cells.The pars intermedia of the pituitary gland of teleosts is unusual in that it contains two different endocrine cell types. From physi ological and immunohistochemical studies we have concluded that the predominant cell type in the pars intermedia of Sarotherodon mossambicus is comparable to the endocrine cells of the pars intermedia of other vertebrates which produce MSH (Van Eys, 1980a;Van Eys and Van den Oetelaar, 1981;Van Eys and Peters, 1981). The second cell type of the pars intermedia, the PAS positive cells, are unique to tele osts and have been implicated, inter alia, in the endocrine control of background adap tation, osmoregulation, and calcium me tabolism (Baker and Ball, 1970;Ball and 1 To whom correspondence should be addressed. Batten, 1981;Malo-Michele, 1975, 1977Olivereau, 1969;Olivereau et al., 1980Olivereau et al., , 1981Pang et al., 1973;Van Eys, 1980b). However, the techniques used to study the function of the PAS positive cells were lim ited to light-and electron microscopy and measurements of cell and nuclear volumes, since nothing is known about the chemical nature of the cellular products. This situa tion hampers further investigations con cerning the function of the PAS positive cells, so the main purpose of the present investigation was to identify the ...

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This study approaches the question of whether angiotensin II (AngII) and transforming growth factor beta (TGF-beta) are important mediators for mesangial heparan sulfate proteoglycan (HSPG) production. This might explain the beneficial effects of angiotensin-converting enzyme inhibitors observed in several kidney diseases independent from their hemodynamic effects. Metabolic-labeling studies revealed that AngII induced a decrease of HSPG synthesis with decreases in N-sulfation of the glycosaminoglycan side chains. ELISA measurements with a heparan sulfate (HS)-specific monoclonal antibody confirmed that AngII decreased HS production. AngII increased TGF-beta production in a dose-dependent fashion. Specific mRNA for the large basement membrane HSPG (perlecan) decreased, whereas mRNA for TGF-beta increased after incubation with AngII. Blockade of the Subtype 1 Ang-II receptor (ATR1) reversed both the effects of AngII on HSPG and TGF-beta production. Coincubation of the mesangial cells with neutralizing antibodies against TGF-beta significantly reduced the production of HS as compared with control and AngII. These results indicate that the decrease in HS synthesis induced by AngII is not mediated by an increase in TGF-beta, but on the contrary, the increase in TGF-beta partially counteracts the inhibition of HS production by AngII. Considering the important role of HSPG in maintaining the glomerular charge barrier, cell proliferation, and matrix interaction, downregulation of the production of this molecule by increased local AngII concentrations could have important consequences, such as albuminuria and matrix expansion.

In the cichlid fish Oreochromis mossambicus prolactin cell activity is inversely related to the osmolarity and the Ca:~ concentration of the ambient water. Prolactin cell activity was estimated, at the end of a 3-week experimental period, by determination of the rate of prolactin synthesis during incubation of the rostral parts of the pituitary gland, in the pres ence of 13HJlysine. Since the secretory activity of isolated prolactin cells is known to be inversely related to the osmolarity of the incubation medium, the possibility was investi gated that the effects of changes in ionic composition of the ambient water on prolactin secretion in vivo are mediated by changes in osmolarity of the blood plasma. No support was found for this hypothesis. In fish exposed to high water osmolarities prolactin cell activity was reduced, while plasma osmolarity increased. In contrast, at high Ca:~ con centrations of the water, when prolactin secretion was inhibited to a similar extent, plasma osmolarity was significantly reduced. Although direct effects of plasma osmolarity on pro lactin cells cannot be excluded completely, it is unlikely that plasma osmolarity is the predominant factor in the control of prolactin cell activity in situ. The physiological signif icance of the capacity of isolated prolactin cells to respond to changes in osmolarity of the ambient medium-a capacity shared with some other endocrine cell types-is therefore unclear. V 1985 Academic Press. Inc.In general there is consensus about the osmolarity of the water as an important am bient factor controlling prolactin secretion in fish (Ensor and Ball, 1972; Dubourg ct cil., 1980; W endelaar Bonga and Van der Meij, 1981). For species such as stickle backs and the cichlid O reochrom is mosscimhicus (further called tilapia), the water concentrations of Ca2+ and Mg2 + and the pH of the water are important additional factors (W endelaar Bonga, 1978;Ogasawara and Yamada, 1979; Van der Meij, 1980, 1981; Wendelaar Bonga cl ciL, 1983. However, spe cies-specific differences have been reported for the responses of prolactin cells to changes in external Ca:+ levels (Dubourg ct a i, 1983).With respect to the internal control of larity. There is ample evidence for the pres ence of hypothalamic control (Wigham ct ul., 1975; Peter and M cKeown, 1975;Ball, 1981). The osm olarity of blood plasm a could be a factor in mediating the effects of the osmolarity of the water on prolactin se cretion (Sage, 1968; N ag ah am a ct cil., 1975), since prolactin cells in vitro respond to osm olarity of the incubation m edium (Sage, 1968; N agaham a ct cil., 1975; Wigham ct cil., 1977; Grau ct cil., 1981).However it should be stressed that the ev idence supporting this hypothesis is indi rect and based on the study of prolactin cells that were deprived of their hypotha lamic connections. The question remains to be answered whether prolactin cells in situ can respond autonomously to plasma os molarity if the hypothalamic control mechprolactin secretion, two mechanisms have anisms a...