Interleukin-6 stimulates thrombopoiesis through thrombopoietin: role in inflammatory thrombocytosis

Baseline platelet production is dependent on thrombopoietin (TPO). TPO is c onstitutively produced and primarily regulated by receptor-mediated uptake by platelets. Inflammatory thrombocytosis is thought to be related to incre ased interleukin-6 (IL-6) levels. To address whether IL-6 might act through TPO to increase platelet counts, TPO was neutralized in vivo in C57BL/10 m ice treated with IL-6, and hepatic TPO mRNA expression and TPO plasma level s were studied. Transcriptional regulation of TPO mRNA was studied in the h epatoblastoma cell line HepG2. Furthermore, TPO plasma levels were determin ed in IL-6-treated cancer patients. It is shown that IL-6-induced thrombocy tosis in C57BL/10 mice is accompanied by enhanced hepatic TPO mRNA expressi on and elevated TPO plasma levels. Administration of IL-6 to cancer patient s results in a corresponding increase in TPO plasma levels. IL-6 enhances T PO mRNA transcription in HepG2 cells. IL-6-induced thrombocytosis can be ab rogated by neutralization of TPO, suggesting that IL-6 induces thrombocytos is through TPO. A novel pathway of TPO regulation by the Inflammatory media tor IL-6 is proposed, indicating that the number of platelets by themselves might not be the sole determinant of circulating TPO levels and thus of th rombopoiesis. This regulatory pathway might be of relevance for the underst anding of reactive thrombocytosis. (C) 2001 by The American Society of Hema tology.