title: Antigen-presenting dendritic cells as regulators of the growth of thyrocytes: a role of interleukin-1beta and interleukin-6.
abstract: An accumulation of antigen-presenting dendritic cells (DC) in the thyroid gland, followed by thyroid autoimmune reactivity, occurs in normal Wistar rats during iodine deficiency, and spontaneously in diabetic-prone Biobreeding rats. This intrathyroidal DC accumulation coincides with an enhanced growth rate and metabolism of the thyrocytes, suggesting that both phenomena are related. Because DC are known to regulate the hormone synthesis and growth in other endocrine systems (i.e. the pituitary, the ovary, and the testis), we tested the hypothesis that DC, known for their superb accessory cell function in T cell stimulation, act as regulators of thyrocyte proliferation (and hormone secretion). We investigated the effect of (Nycodenz density gradient) purified splenic DC from Wistar rats on the growth rate of and thyroid hormone secretion by Wistar thyroid follicles (collagenase dispersion) in culture. Various numbers of DC and follicles were cocultured during 24 h. The proliferative capacity of thyrocytes was measured by adding tritiated thymidine (3H-TdR) and bromodeoxyuridine, the hormone secretion into the culture fluid was measured by using a conventional T3 RIA. Furthermore, antibodies directed against interleukin-1beta (IL-1beta), IL-6, and tumor necrosis factor-alpha (TNF-alpha) were added to these cocultures to determine the role of these cytokines in a possible DC regulation of thyrocyte growth. Cocultures were also carried out in the presence of antimajor histocompatibility complex-class I (MHC I), anti-MHC II, antiintercellular adhesion molecule-1 (ICAM-1), and antilymphocyte function-associated antigen-1alpha (LFA-1alpha) antibodies to possibly interfere with DC-thyrocyte interactions. The addition of DC to thyroid follicles clearly inhibited their 3H-TdR uptake, particularly at a 10:1 ratio, in comparison to follicle cultures alone, both under basal conditions and after TSH stimulation (75 +/- 7% and 49 +/- 11% reduction, respectively, n = 4). The follicle T3 secretion (after TSH stimulation) was also suppressed by DC in this system, but to a lesser extent (at best at an 1:1 ratio, 25 +/- 7% reduction, n = 4). The DC-induced inhibition of thyroid follicle growth was totally abrogated after addition of anti-IL-1beta antibodies; anti-IL-6 only had effect on the DC inhibition of non-TSH-stimulated thyrocytes, whereas anti-TNF-alpha demonstrated no effect at all. The antibodies to MHC and to adhesion molecules had also no effect on this DC-induced growth inhibition. The effect of the different anti-cytokine and anti-adhesion antibodies on the T3 secretion from thyroid follicles was not investigated. The clear inhibition of thyrocyte growth by splenic DC (classical antigen-presenting cells) again demonstrates the regulatory role of DC in endocrine systems. Proinflammatory cytokines such as IL-1beta and IL-6 are important mediators in this regulation. The here shown dual role of DC represents a link between the immune and endocrine system, which may form the gateway to the understanding of the initiation of thyroid autoimmune reactions and the thyroid autoimmune phenomena seen in iodine deficiency.
authors.affiliation: Department of Immunology, Erasmus University Rotterdam, The Netherlands. simons@immu.fgg.eur.nl
authors.forename: P J
authors.initials: PJ
authors.lastname: Simons
authors.forename: F G
authors.initials: FG
authors.lastname: Delemarre
authors.forename: H A
authors.initials: HA
authors.lastname: Drexhage
mesh_terms: D000818:Animals; D000906:Antibodies / Q000276:immunology; D000938:Antigen-Presenting Cells / Q000502:physiology*; D015815:Cell Adhesion Molecules / Q000276:immunology; D002450:Cell Communication / Q000276:immunology / Q000502:physiology; D002455:Cell Division / Q000502:physiology; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000502:physiology*; D007375:Interleukin-1 / Q000502:physiology*; D015850:Interleukin-6 / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D013154:Spleen / Q000166:cytology; D013936:Thymidine / Q000037:antagonists & inhibitors / Q000493:pharmacokinetics; D013961:Thyroid Gland / Q000166:cytology* / Q000378:metabolism; D014284:Triiodothyronine / Q000378:metabolism
chemical_list: D000906:Antibodies; D015815:Cell Adhesion Molecules; D007375:Interleukin-1; D015850:Interleukin-6; D014284:Triiodothyronine; D013936:Thymidine