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Diabetes Care 27:844-845, 2004
© 2004 by the American Diabetes Association, Inc.

Letters: Observations

Tumor Necrosis Factor-{alpha} Is Associated With Increased Protein C Activation in Nonobese Type 2 Diabetic Patients

Yutaka Yano, MD1, Esteban C. Gabazza, MD1, Nagako Kitagawa, MD1, Nelson E. Bruno, MD1, Kazutaka Matsumoto, MD1, Kaname Nakatani, MD2, Rika Araki, MD3, Akira Katsuki, MD1, Yukihiko Adachi, MD1 and Yasuhiro Sumida, MD1

1 Third Department of Internal Medicine, Mie University School of Medicine, Tsu, Mie, Japan
2 Laboratory Medicine, Mie University School of Medicine, Tsu, Mie, Japan
3 Department of Internal Medicine, National Mie Hospital, Tsu, Mie, Japan

Address correspondence to Dr. Yutaka Yano, Third Department of Internal Medicine, Mie University School of Medicine, Edobashi 2-174, Tsu, Mie 514-8507, Japan. E-mail: yanoyuta{at}clin.medic.mie-u.ac.jp

Tumor necrosis factor-{alpha} (TNF-{alpha}) plays a critical role in the pathogenesis of vascular injury in diabetic patients (1). Increased circulating levels of TNF-{alpha} have been reported in diabetic patients (2,3). Hyperglycemia stimulates TNF-{alpha} secreted from monocytes and endothelial cells (4,5). Moreover, TNF-{alpha} may cause vascular injury by affecting the balance between coagulation and fibrinolysis. For example, TNF-{alpha} stimulates the expression of tissue factor that is the initiator of blood coagulation activation and the secretion of plasminogen activator inhibitor-1 that inhibits fibrinolysis (1).

Activated protein C (APC) is a serine protease that inhibits activation of the blood coagulation system by proteolytically inactivating factors Va and VIIIa and by stimulating fibrinolysis (6,7). APC may indirectly promote fibrinolysis by inhibiting thrombin generation and by inhibiting the action of plasminogen activator inhibitor-1 (8). Recently, it was reported that APC has an anti-inflammatory effect and that it inhibits vascular injury induced by TNF-{alpha} (9,10). Therefore, APC may inhibit hypercoagulability and inflammatory response induced by TNF-{alpha}, which increases during hyperglycemia. However, the relationship between circulating TNF-{alpha} and APC levels has not yet been reported in diabetic patients. In the present study, we investigated the relationship between the plasma levels of TNF-{alpha} and APC in normotensive type 2 diabetic patients.

Twenty-four normotensive (<140/90 mmHg) nonobese type 2 diabetic patients (16 men and 8 women, aged 53.0 ± 2.0 years [mean ± SE], BMI 23.1 ± 0.5 kg/m2, diabetes duration 6.7 ± 1.1 years, systolic blood pressure 131.0 ± 2.1 mmHg, diastolic blood pressure 78.1 ± 1.9 mmHg, fasting blood glucose levels 7.8 ± 0.32 mmol/l, and HbA1c 8.9 ± 0.3%) enrolled in the present study. All patients had normoalbuminuria and were being treated with diet therapy alone. Data obtained in 18 age-matched nonobese healthy subjects (14 men and 4 women) were used as control. The plasma levels of TNF-{alpha} were measured with an enzyme immunosorbent assay (EIA) kit (TNF-{alpha} EIA kit; Biosourse International, Camarillo, TX). As a marker of APC generation, APC-protein C inhibitor (PCI) complex was measured by enzyme-linked immunoassay as previously described (11). Protein C (PC) antigen was measured by solid-phase immunoassay as previously described (11). Total protein S (PS), a cofactor for activation of PC, was measured as previously reported (11). As a marker of coagulation activation, the plasma levels of thrombin-antithrombin complex (TAT) were measured by an EIA using anti-human monoclonal TAT antibody. As a marker of fibrinolysis, D-dimer was measured with a commercial EIA kit (D-dimer test F; Kokusai Shiyaku, Kobe, Japan). The plasma levels of TNF-{alpha} were significantly higher (1.60 ± 0.13 vs. 0.81 ± 0.32 pg/ml, P < 0.05) in diabetic patients than in normal subjects. The plasma levels of APC-PCI were significantly higher (4.63 ± 0.38 vs. 2.58 ± 0.60 pmol/l, P < 0.005) in diabetic patients than in normal subjects. There was a significant and positive correlation between the plasma levels of TNF-{alpha} and TAT in diabetic patients (r = 0.46, P < 0.05). There was a significant and inverted correlation between the plasma levels of TNF-{alpha} and D-dimer in diabetic patients (r = -0.52, P < 0.01). The plasma levels of TNF-{alpha} were positively and significantly correlated with the plasma levels of APC-PCI (r = 0.42, P < 0.05) in diabetic patients. There was no significant correlation between TNF-{alpha} and PC antigen (r = 0.33) and PS levels (r = 0.07).

The elevation of TNF-{alpha} in diabetic patients observed in our study is in agreement with previous data (2,3). Proportional correlation of TNF-{alpha} with TAT and inverse correlation with D-dimer suggests the occurrence of hypercoagulability and hypofibrinolysis in association with TNF-{alpha} in diabetic patients. Interestingly, the circulating levels of TNF-{alpha} were significantly correlated with APC-PCI complex, a marker of APC generation. These data suggest that APC may regulate fibrinolysis and hypercoagulability induced by TNF-{alpha}. It was reported that APC reduces vascular injury and hypercoagulability by inhibiting TNF-{alpha} production in rats treated with lipopolysaccaride (LPS) (9). APC may also inhibit production of TNF-{alpha} in LPS-treated culture cells (10). Another report (12) demonstrated that APC activates protease activated receptor-1 and induced gene expression of A20 (TNF-{alpha} induced protein 3) and tristetraprolin. A20 is cytoplasmic zinc finger protein that inhibits TNF-{alpha}-induced nuclear factor {kappa}B activity (13). Tristetraprolin inhibits TNF-{alpha} production by destabilizing its messenger RNA (14). Therefore, these mechanisms may be involved in the protective effect of APC in diabetic patients. However, the significant increase of TNF-{alpha} in diabetic patients suggests that APC may not be sufficient for regulating TNF-{alpha} expression. In brief, PC activation may be important for the regulation of TNF-{alpha}-induced coagulation abnormalities and inflammation in diabetes.

References

  1. Okajima K: Regulation of inflammatory responses by natural anticoagulants. Immunol Rev 184:258–274, 2001[Medline]
  2. Esposito K, Nappo F, Marfella R, Giugliano G, Giugliano F, Ciotola M, Quagliaro L, Ceriello A, Giugliano D: Inflammatory cytokine concentrations are acutely increased by hyperglycemia in humans: role of oxidative stress. Circulation 106:2067–2072, 2002[Abstract/Free Full Text]
  3. Diamant M, Nieuwland R, Pablo RF, Sturk A, Smit JW, Radder JK: Elevated numbers of tissue-factor exposing microparticles correlate with components of the metabolic syndrome in uncomplicated type 2 diabetes mellitus. Circulation 106:2442–2447, 2002[Abstract/Free Full Text]
  4. Shanmugam N, Reddy MA, Guha M, Natarajan R: High glucose-induced expression of proinflammatory cytokine and chemokine genes in monocytic cells. Diabetes 52:1256–1264, 2003[Abstract/Free Full Text]
  5. Amore A, Cirina P, Mitola S, Peruzzi L, Gianoglio B, Rabbone I, Sacchetti C, Cerutti F, Grillo C, Coppo R: Nonenzymatically glycated albumin (Amadori adducts) enhances nitric oxide synthase activity and gene expression in endothelial cells. Kidney Int 51:27–35, 1997[Medline]
  6. Bajzar L: Thrombin activatable fibrinolysis inhibitor and an antifibrinolytic pathway. Arterioscler Thromb Vasc Biol 20:2511–2518, 2000[Abstract/Free Full Text]
  7. Esmon CT: Protein C anticoagulant pathway and its role in controlling microvascular thrombosis and inflammation. Crit Care Med 29 (Suppl.):S48–S52, 2001
  8. Sakata Y, Loskutoff DJ, Gladson CL, Hekman CM, Griffin JH: Mechanism of protein C-dependent clot lysis: role of plasminogen activator inhibitor. Blood 68:1218–1223, 1986[Abstract/Free Full Text]
  9. Murakami K, Okajima K, Uchiba M, Johno M, Nakagaki T, Okabe H, Takatsuki K: Activated protein C prevents LPS-induced pulmonary vascular injury by inhibiting cytokine production. Am J Physiol 272 (Suppl.):L197–L202, 1997
  10. Yuksel M, Okajima K, Uchiba M, Horiuchi S, Okabe H: Activated protein C inhibits lipopolysaccharide-induced tumor necrosis factor-alpha production by inhibiting activation of both nuclear factor-kappa B and activator protein-1 in human monocytes. Thromb Haemost 88:267–273, 2002[Medline]
  11. Hori Y, Gabazza EC, Yano Y, Katsuki A, Suzuki K, Adachi Y, Sumida Y: Insulin resistance is associated with increased circulating level of thrombin-activatable fibrinolysis inhibitor in type 2 diabetic patients. J Clin Endocrinol Metab 87:660–665, 2002[Abstract/Free Full Text]
  12. Riewald M, Petrovan RJ, Donner A, Mueller BM, Ruf W: Activation of endothelial cell protease activated receptor 1 by the protein C pathway. Science 296:1880–1882, 2002[Abstract/Free Full Text]
  13. Lee EG, Boone DL, Chai S, Libby SL, Chien M, Lodolce JP, Ma A: Failure to regulate TNF-induced NF-kappaB and cell death responses in A20-deficient mice. Science 289:2350–2354, 2000[Abstract/Free Full Text]
  14. Carballo E, Lai WS, Blackshear PJ: Feedback inhibition of macrophage tumor necrosis factor-alpha production by tristetraprolin. Science 281:1001–1005, 1998[Abstract/Free Full Text]

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