ANTIGEN-PRESENTING DENDRITIC CELLS AS REGULATORS OF THE GROWTH OF THYROCYTES - A ROLE OF INTERLEUKIN-1-BETA AND INTERLEUKIN-6

An accumulation of antigen-presenting dendritic cells (DC) in the thyr oid gland, followed by thyroid autoimmune reactivity, occurs in normal Wistar rats during iodine deficiency, and spontaneously in diabetic-p rone Biobreeding rats. This intrathyroidal DC accumulation coincides w ith an enhanced growth rate and metabolism of the thyrocytes, suggesti ng that both phenomena are related. Because DC are known to regulate t he hormone synthesis and growth in other endocrine systems (i.e. the p ituitary, 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 s plenic DC from Wistar rats on the growth rate of and thyroid hormone s ecretion by Wistar thyroid follicles (collagenase dispersion) in cultu re. Various numbers of DC and follicles were cocultured during 24 h. T he proliferative capacity of thyrocytes was measured by adding tritiat ed thymidine (H-3-TdR) and bromodeoxyuridine, the hormone secretion in to the culture fluid was measured by using a conventional T-3 RIA. Fur thermore, antibodies directed against interleukin-1 beta (IL-1 beta), 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 r egulation of thyrocyte growth. Cocultures were also carried out in the presence of antimajor histocompatibility complex-class I (MHC I), ant i-MHC II, antiintercellular adhesion molecule-1 (ICAM-1), and antilymp hocyte function-associated antigen-1 alpha (LFA-1 alpha) antibodies to possibly interfere with DC-thyrocyte interactions. The addition of DC to thyroid follicles clearly inhibited their H-3-TdR uptake, particul arly at a 10:1 ratio, in comparison to follicle cultures alone, both u nder basal conditions and after TSH stimulation (75 +/- 7% and 49 +/- 11% reduction, respectively, n = 4). The follicle T-3 secretion (after TSH stimulation) was also suppressed by DC in this system, but to a l esser extent (at best at an 1:1 ratio, 25 +/- 7% reduction, n = 4). Th e DC-induced inhibition of thyroid follicle growth was totally abrogat ed after addition of anti-IL-lp antibodies; IL-6 only had effect on th e DC inhibition of non-TSH-stimulated thyrocytes, whereas anti-TNF-alp ha demonstrated no effect at all. The antibodies to MHC and to adhesio n molecules had also no effect on this DC-induced growth inhibition. T he effect of the different anticytokine and anti-adhesion antibodies o n the T-3 secretion from thyroid follicles was not investigated. The c lear inhibition of thyrocyte growth by splenic DC (classical antigen-p resenting cells) again demonstrates the regulatory role of DC in endoc rine systems. Proinflammatory cytokines such as IL-1 beta and IL-6 are important mediators in this regulation. The here shown dual role of D C represents a link between the immune and endocrine system, which may form the gateway to the understanding of the initiation of thyroid au toimmune reactions and the thyroid autoimmune phenomena seen in iodine deficiency.