Elevated Serum Thrombopoietin and Interleukin-6 Concentrations in Thrombocytosis Associated with Inflammatory Bowel Disease

Heits, Frank; Stahl, Maren; Ludwig, D.; Stange, Eduard F.; Jelkmann, Wolfgang

doi:10.1089/107999099313604

Cited by 80 publications

(62 citation statements)

References 30 publications

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“…Leukocytosis is a recognized component of enterocolitis pathogenesis and has been previously noted in an adult zebrafish enterocolitis model (Meuret et al, 1978;Heits et al, 1999;Brugman et al, 2009) (Fig. 5A).…”

Section: Zebrafish Larvae Mount a Leukocytic Response During Tnbs-indmentioning

confidence: 53%

A chemical enterocolitis model in zebrafish larvae that is dependent on microbiota and responsive to pharmacological agents

Oehlers

Flores

Okuda

et al. 2010

Developmental Dynamics

120

168

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Inflammatory bowel disease (IBD) results from dysfunctional interactions between the intestinal immune system and microbiota, influenced by host genetic susceptibility. Because a key feature of the pathology is intestinal epithelial damage, potential disease factors have been traditionally analyzed within the background of chemical colitis models in mice. The zebrafish has greatly complemented the mouse for modeling aspects of disease processes, with an advantage for high content drug screens. Larval zebrafish exposed to the haptenizing agent trinitrobenzene sulfonic acid (TNBS) displayed impaired intestinal homeostasis and inflammation reminiscent of human IBD. There was a marked induction of pro-inflammatory cytokines, the degradative enzyme mmp9 and leukocytosis. Enterocolitis was dependent on microbiota and Toll-like receptor signaling, that can be ameliorated by antibiotic and anti-inflammatory drug treatments. This system will be useful to rapidly interrogate in vivo the biological significance of the IBD candidate genes so far identified and to carry out pharmacological modifier screens. Developmental Dynamics 240:288-298,

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Section: Zebrafish Larvae Mount a Leukocytic Response During Tnbs-indmentioning

confidence: 53%

A chemical enterocolitis model in zebrafish larvae that is dependent on microbiota and responsive to pharmacological agents

Oehlers

Flores

Okuda

et al. 2010

Developmental Dynamics

120

168

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“…Several lines of evidence support a decisive role for IL-6 15,50 : IL-6 serum levels are elevated in patients with reactive thrombocytosis compared to levels in healthy controls 15,16,51,52 ; IL-6 knockout mice show a severely impaired acute-phase response 7 ; and transgenic overexpression of IL-6 4 and administration of recombinant IL-6 to mice, 4,53 primates, 14,54 and humans [8][9][10][11][12][13][14] results in an increase in the circulating platelet count. In consideration of data presented in this paper, we propose that IL-6 mediates reactive thrombocytosis primarily through TPO.…”

Section: Discussionmentioning

confidence: 99%

“…They showed that following hip-replacement surgery, the increase in TPO serum levels-correlating with IL-6-preceded the peak in platelet counts by 11 days. Accordingly, Heits et al 51,52 recently reported concomitant elevations of IL-6 and TPO plasma levels accompanied by elevated platelet counts in patients with inflammatory bowel disease 51 and solid tumors. 52 We show that the administration of IL-6 to patients with cancer results in a substantial increase in TPO plasma levels.…”

Section: Il-6 Induces Thrombocytosis Through Tpo 2723mentioning

confidence: 99%

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

Kaser

Brandacher

Steurer

et al. 2001

Blood

567

390

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Baseline platelet production is dependent on thrombopoietin (TPO). TPO is constitutively produced and primarily regulated by receptor-mediated uptake by platelets. Inflammatory thrombocytosis is thought to be related to increased 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 mice treated with IL-6, and hepatic TPO mRNA expression and TPO plasma levels were studied. Transcriptional regulation of TPO mRNA was studied in the hepatoblastoma cell line HepG2. Furthermore, TPO plasma levels were determined in IL-6-treated cancer patients. It is shown that IL-6-induced thrombocytosis in C57BL/10 mice is accompanied by enhanced hepatic TPO mRNA expression and elevated TPO plasma levels. Administration of IL-6 to cancer patients results in a corresponding increase in TPO plasma levels. IL-6 enhances TPO mRNA transcription in HepG2 cells. IL-6-induced thrombocytosis can be abrogated by neutralization of TPO, suggesting that IL-6 induces thrombocytosis through TPO. A novel pathway of TPO regulation by the inflammatory mediator 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 thrombopoiesis. This regulatory pathway might be of relevance for the understanding of reactive thrombocytosis. IntroductionThrombocytosis can be classified into primary and secondary forms. Whereas primary thrombocytosis is observed in myeloproliferative syndromes, secondary or reactive thrombocytosis is noted in numerous clinical situations, 1 especially in association with inflammatory states of either infectious or noninfectious origin such as trauma and malignancy. 2,3 The extent to which mediators of the immune or hematopoietic system are involved in the regulation of the circulating platelet count in these conditions is insufficiently understood.Interleukin-6 (IL-6) plays a prominent role in inflammatory and neoplastic diseases. 4-6 Accordingly, mice deficient in IL-6 show a severely impaired acute-phase response. 7 Administration of IL-6 to humans has been associated with an increase in circulating platelet counts. [8][9][10][11][12][13][14] Furthermore, serum levels of IL-6 were significantly higher in patients with reactive thrombocytosis than in control patients. 15,16 Whether the thrombopoietic effect of IL-6 in vivo is caused by direct stimulation of hematopoietic progenitor cells or is indirectly mediated is unknown.Thrombopoietin (TPO), the ligand of the c-mpl proto-oncogene, is the primary regulator of proliferation and differentiation of megakaryocyte progenitors. [17][18][19][20][21][22][23] Mice rendered deficient in TPO or TPO receptor by gene targeting show severe thrombocytopenia, with platelet counts reduced by approximately 90%. 22,24 Treatment of mice, nonhuman primates, and humans with recombinant TPO or recombinant megakaryocyte growth and development factor, which constitutes a truncated, biologically active form of TPO, results in sig...

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“…Several mechanisms can be responsible for this, including abnormal coagulation activity [2][3][4][5][6], disturbances of the fibrinolytic pathway [7] and thrombocytosis [8].…”

Section: Introductionmentioning

confidence: 99%

Platelets and Anticoagulant Capacity in Patients with Inflammatory Bowel Disease

Larsen

Nielsen²,

Fredholm³

et al. 2002

Pathophysiol Haemos Thromb

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Patients with inflammatory bowel disease (IBD) are susceptible to thromboembolic complications. Several mechanisms can be responsible, including abnormal regulation of coagulation activity, disturbances of fibrinolysis, inflammatory reactions and thrombocytosis. The aim of this study was to assess hemostatic alterations in these parameters during exacerbation of disease. We studied disease activity in 99 IBD patients receiving anti-inflammatory therapy, in relation to: procoagulant markers, i.e. prothrombin fragment F1 + 2 (F1 + 2), D-dimer and platelet count, anticoagulant markers, i.e. protein C, protein S and antithrombin, and a mediator of inflammation (IL-6). Coagulation activity and platelet count were increased during active disease in IBD patients compared with those in a state of remission. The IL-6 concentrations were positively correlated with disease activity and thrombocytosis in patients with ulcerative colitis, but no association with the anticoagulant capacity could be demonstrated except for a decrease in protein C during high disease activity.

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Elevated Serum Thrombopoietin and Interleukin-6 Concentrations in Thrombocytosis Associated with Inflammatory Bowel Disease

Cited by 80 publications

References 30 publications

A chemical enterocolitis model in zebrafish larvae that is dependent on microbiota and responsive to pharmacological agents

A chemical enterocolitis model in zebrafish larvae that is dependent on microbiota and responsive to pharmacological agents

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

Platelets and Anticoagulant Capacity in Patients with Inflammatory Bowel Disease

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