Possible Pathogenetic Relevance of Interleukin‐1β in “Destructive” Organ‐specific Autoimmune Disease (Hashimoto's Thyroiditis)

Abstract

Thyroid follicular cells (TFC) abundantly express a variety of immunologically relevant surface molecules in Hashimoto's thyroiditis (HT), for example, MHC antigens and adhesion molecules such as ICAM-1. Cytokines produced by infiltrating type 1 helper and cytotoxic T cells are importantly involved in de novo expression or up-regulation of such molecules. We recently demonstrated that TFC from HT patients almost invariably bear on their surface two additive functional molecules: Fas/Apo1/CD95, an important participant in apoptosis, and B7.1, a member of a family of "co-stimulatory" molecules that are crucial for efficient antigen presentation. To date, 12 out of 14 surgical HT thyroid specimens that we studied by immunohistochemistry showed B7.1-positive TFC, and all showed Fas-positive TFC, different from Graves' disease (GD) or nonautoimmune specimens. We have investigated the role of a number of cytokines (IL-1 beta, TNF-alpha, IL-4, IL-6, IL-10, IL-12, TGF-beta 1, IFN-gamma) in regulating B7.1 and Fas expression. The experiments were performed by immunofluorescence flow cytometry on TFC purified from nontoxic goiter specimens which were Fas- and B7.1-negative at baseline, and one B7.1/Fas-positive HT specimen. IFN-gamma (500 U/mL) and TNF-alpha (200 ng/mL) were unable to induce de novo expression of B7.1 or Fas on cultured TFC. At higher doses (2000 U/mL and 800 ng/mL, respectively), they were unable to induce B7.1, but potentiated the spontaneous expression of Fas. Type 2 cytokines (IL-4 and IL-10) were unable to induce Fas or B7.1 on TFC at all, or to down-regulate Fas or B7.1 when expressed. On the other hand, IL-1 beta was the only cytokine able to induce Fas expression on Fas-negative TFC at doses ranging from 100 to 1000 pg/mL. Moreover, at a dose of 400 pg/mL, it was also able to induce B7.1. We demonstrated by immunohistochemistry that IL-1 beta is abundantly present on HT thyroids, including follicular structures. It is conceivable that IFN-gamma, or other cytokines secreted by infiltrating T-lymphocytes, are able to promote IL-1 beta secretion by TFC. In conclusion, a crucial role of IL-1 beta in "destructive" organ-specific autoimmunity may be suggested both for the perpetuation of the autoimmune reaction (induction of efficient autoantigen presentation by TFC, via co-stimulatory molecules) and in induction of tissue damage via "suicide" Fas/FasL-mediated TFC interaction.

A Role for IL-15 in Driving the Onset of Spontaneous Autoimmune Thyroiditis?

“…Not surprisingly, considering the implication of T cell-mediated cytotoxic processes in the pathogenesis of Hashimoto's thyroiditis after the lymphoid infiltration of the thyroid, the proinflammatory cytokines IL-1␤, IL-6, and IL-8 have all been shown to be expressed in the thyroids of patients suffering from the disease (26,(33)(34)(35)(36). This report shows that these cytokines are expressed in the thyroids of OS chickens before the onset of the lymphoid infiltration.…”

Association of the −31C/T functional polymorphism in the interleukin-1β gene with the intractability of Graves' disease and the proportion of T helper type 17 cells

“…On the other hand, we expected that genetic producibility of IL-1b may also relate to the severity of HD, because IL-1b induces the expression of some chemokines and surface molecules on thyrocytes in vitro and seems to enhance the inflammatory destruction of thyrocytes [35][36][37]. However, the IL-1b -31C/T polymorphism was not associated with the severity of HD (Table 1), suggesting no association between the genetic producibility of IL-1b and the severity of HD.…”

Inflammatory cytokine regulation of TRAIL-mediated apoptosis in thyroid epithelial cells

“…18 ± 23 Regulation of death receptor pathways in the thyroid may be a potential mechanism in which inflammatory cytokines might act to promote disease progression. Several groups, including our own, have shown the influence of inflammatory cytokines in Fas-mediated apoptosis of cultured thyroid cells 11,12,24,25 and reviewed in Borgerson et al 14 We have also shown that thyroid epithelial cells (TECs) are susceptible to TRAIL-mediated apoptosis after pretreatment with cycloheximide (CHX) and that TRAIL itself is expressed by the TECs treated with IFNg, TNFa or IL1b. 26 Combined, this data suggests that TRAIL-mediated apoptosis may have a role in autoimmune thyroiditis.…”