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Extracellular Adenosine 5'-Triphosphate Modulates Interleukin-6 Production by Human Thyrocytes through Functional Purinergic P2 Receptors

Department of Internal Medicine (N.C., F.M., E.S., S.C., E.F., A.S.), University of Pisa, I-56100 Pisa; and Department of Experimental and Diagnostic Medicine (D.F., M.G.C., S.G., C.P., F.D.V.), Section of General Pathology, Interdisciplinary Center for the Study of Inflammation, University of Ferrara, I-44100 Ferrara, Italy

Address all correspondence and requests for reprints to: Anna Solini, M.D. Ph.D., Department of Internal Medicine University of Pisa, Section of Internal Medicine III, Via Roma 67, I-56100 Pisa. Italy. E-mail: a.solini{at}med.unipi.it.

We investigated the presence of P2 receptors (P2Rs) in human thyrocytes and their possible involvement in the modulation of cytokine release. P2Rs expression was assessed by RT-PCR and, when possible, by immunoblotting. Human primary thyrocytes express the mRNA for the following P2X and P2Y subtypes: P2X₃, P2X₅, P2X₆, P2X₇, and P2Y₁, P2Y₂, P2Y₄, and P2Y₁₁. Stimulation with extracellular nucleotides of fura-2-loaded thyrocytes triggered an intracellular Ca²⁺ signal, suggesting expression of functional receptors. Thyrocytes spontaneously released the proinflammatory cytokine IL-6. The ATP-hydrolyzing enzyme apyrase reduced basal IL-6 release, whereas extracellular ATP dose-dependently increased IL-6 secretion. Uridine 5'-triphosphate was also an effective stimulus, whereas benzoyl-ATP was ineffective, suggesting a P2Y- rather than P2X-modulated response. Finally, TSH reduced both the intracellular Ca²⁺ ([Ca²⁺]_i) rise and IL-6 release triggered by P2Rs stimulation. In conclusion, we provide functional, pharmacological, and biochemical evidence that human primary thyrocytes express P2YR and P2XR subtypes, coupled to increases in ([Ca²⁺]_i) and secretion of IL-6. P2R-dependent modulation of IL-6 release from human thyrocytes suggests a novel mechanism whereby an inflammatory and/or immune-mediated damage can be initiated and amplified in the thyroid.

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