Primate Monocytes - CD14, CD16 - Ziegler-Heitbrock

Thyroid Eye Disease (TED) Monocytes Express a Functional Thyrotropin Receptor and Express Increased IL-6 and IL-8: Possible Mechanistic Implications.

Abstract

PURPOSE: Monocytes are involved in autoimmune diseases, including Graves disease and thyroid eye disease (TED). We studied the expression and function of the thyrotropin receptor (TSHR) in all subsets (classical: CD14++, CD16-; intermediate: CD14++, CD16+; nonclassical: CD14+, CD16++), because the functional consequences of TSHR signaling induced by TSHR autoantibodies may contribute to TED. METHODS: Flow cytometry was used to determine TSHR, intracellular IL-6 and IL-8, Akt phosphorylation, caspase 3, and reactive oxygen species production by monocytes from isolated peripheral blood mononuclear cells. Real-time polymerase chain reaction was used to measure mRNA of TSHR, IL-6, and IL-8 from enriched monocytes. RESULTS: Monocytes express TSHR, with expression induced by thyroid-stimulating hormone and Graves disease-specific autoantibody M22. Basal phosphorylated Akt levels were greater in monocytes from patients with TED. Thyrotropin receptor signaling was mediated through Akt. Monocytes produced reactive oxygen species and cytokines IL-6 and IL-8 in response to TSHR signaling. Cytokine expression was greater in classical and intermediate monocytes from patients with TED than those from healthy controls stimulated with thyroid-stimulating hormone and M22. Thyroid-stimulating hormone and M22 promoted apoptosis in intermediate and nonclassical monocytes but not classical monocytes. Apoptosis of nonclassical and intermediate monocytes appears mediated through caspase 3 since thyroid-stimulating hormone stimulated caspase 3 activation. CONCLUSION: Our results demonstrate functional TSHR on monocytes, and TSHR signaling stimulates proinflammatory cytokine and reactive oxygen species response, with increased response in monocytes from patients with TED. This suggests an important role for stimulatory autoantibodies-TSHR interaction in monocyte function and activation, which may be relevant to TED development.