Elevated Serum Levels of Soluble TNF Receptors and Adhesion Molecules Are Associated with Diabetic Retinopathy in Patients with Type-1 Diabetes

Overview

Journal Mediators Inflamm

Publisher Wiley

Specialties Biochemistry
Pathology

Date 2015 Sep 5

PMID 26339132

Citations 28

Authors

Shruti Sharma

Sharad Purohit

Ashok Sharma

Diane Hopkins

Leigh Steed

Bruce Bode

Stephen W Anderson

Ruth Caldwell

Jin-Xiong She

Affiliations

Soon will be listed here.

Abstract

Aims: To examine the association of the serum levels of TNF receptors, adhesion molecules, and inflammatory mediators with diabetic retinopathy (DR) in T1D patients.

Methods: Using the multiplex immunoassay, we measured serum levels of eight proteins in 678 T1D subjects aged 20-75 years. Comparisons were made between 482 T1D patients with no complications and 196 T1D patients with DR.

Results: The levels of sTNFR-I, sTNFR-II, CRP, SAA, sgp130, sIL6R, sVCAM1, and sICAM1 were significantly higher in the T1D patients with DR as compared to T1D patients with no complications. Multivariate logistic regression analysis revealed significant association for five proteins after adjustment for age, sex, and disease duration (sTNFR-I: OR = 1.57, sgp130: OR = 1.43, sVCAM1: OR = 1.27, sICAM1: OR = 1.42, and CRP: OR = 1.15). Conditional logistic regression on matched paired data revealed that subjects in the top quartile for sTNFR-I (OR = 2.13), sTNFR-II (OR = 1.66), sgp130 (OR = 1.82), sIL6R (OR = 1.75), sVCAM1 (OR = 1.98), sICAM1 (OR = 2.23), CRP (OR = 2.40) and SAA (OR = 2.03), had the highest odds of having DR.

Conclusions: The circulating markers of inflammation, endothelial injury, and TNF signaling are significantly associated with DR in patients with T1D. TNFR-I and TNFR-II receptors are highly correlated, but DR associated more strongly with TNFR-I in these patients.

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References

Kilpatrick E, Keevil B, Jagger C, Spooner R, Small M . Determinants of raised C-reactive protein concentration in type 1 diabetes. QJM. 2000; 93(4):231-6. DOI: 10.1093/qjmed/93.4.231. View

Hein T, Singh U, Vasquez-Vivar J, Devaraj S, Kuo L, Jialal I . Human C-reactive protein induces endothelial dysfunction and uncoupling of eNOS in vivo. Atherosclerosis. 2009; 206(1):61-8. PMC: 2735606. DOI: 10.1016/j.atherosclerosis.2009.02.002. View

Limb G, Hollifield R, Webster L, Charteris D, CHIGNELL A . Soluble TNF receptors in vitreoretinal proliferative disease. Invest Ophthalmol Vis Sci. 2001; 42(7):1586-91. View

Joussen A, Poulaki V, Mitsiades N, Kirchhof B, Koizumi K, Dohmen S . Nonsteroidal anti-inflammatory drugs prevent early diabetic retinopathy via TNF-alpha suppression. FASEB J. 2002; 16(3):438-40. DOI: 10.1096/fj.01-0707fje. View

Adamis A . Is diabetic retinopathy an inflammatory disease?. Br J Ophthalmol. 2002; 86(4):363-5. PMC: 1771111. DOI: 10.1136/bjo.86.4.363. View

Peter Chase H, Cooper S, Osberg I, Stene L, Barriga K, Norris J . Elevated C-reactive protein levels in the development of type 1 diabetes. Diabetes. 2004; 53(10):2569-73. DOI: 10.2337/diabetes.53.10.2569. View

Taga T, Hibi M, Hirata Y, Yamasaki K, Yasukawa K, Matsuda T . Interleukin-6 triggers the association of its receptor with a possible signal transducer, gp130. Cell. 1989; 58(3):573-81. DOI: 10.1016/0092-8674(89)90438-8. View

Bevilacqua M . Endothelial-leukocyte adhesion molecules. Annu Rev Immunol. 1993; 11:767-804. DOI: 10.1146/annurev.iy.11.040193.004003. View

Ng S, Tan Y, Guy G . Differential induction of the interleukin-6 gene by tumor necrosis factor and interleukin-1. J Biol Chem. 1994; 269(29):19021-7. View

10.

Fasching P, Veitl M, Rohac M, Streli C, Schneider B, Waldhausl W . Elevated concentrations of circulating adhesion molecules and their association with microvascular complications in insulin-dependent diabetes mellitus. J Clin Endocrinol Metab. 1996; 81(12):4313-7. DOI: 10.1210/jcem.81.12.8954033. View

11.

Aderka D . The potential biological and clinical significance of the soluble tumor necrosis factor receptors. Cytokine Growth Factor Rev. 1996; 7(3):231-40. DOI: 10.1016/s1359-6101(96)00026-3. View

12.

Romano M, Sironi M, Toniatti C, Polentarutti N, Fruscella P, Ghezzi P . Role of IL-6 and its soluble receptor in induction of chemokines and leukocyte recruitment. Immunity. 1997; 6(3):315-25. DOI: 10.1016/s1074-7613(00)80334-9. View

13.

Robak T, Gladalska A, Stepien H, Robak E . Serum levels of interleukin-6 type cytokines and soluble interleukin-6 receptor in patients with rheumatoid arthritis. Mediators Inflamm. 1999; 7(5):347-53. PMC: 1781865. DOI: 10.1080/09629359890875. View

14.

McHale J, Harari O, Marshall D, Haskard D . Vascular endothelial cell expression of ICAM-1 and VCAM-1 at the onset of eliciting contact hypersensitivity in mice: evidence for a dominant role of TNF-alpha. J Immunol. 1999; 162(3):1648-55. View

15.

Soedamah-Muthu S, Chaturvedi N, Schalkwijk C, Stehouwer C, Ebeling P, Fuller J . Soluble vascular cell adhesion molecule-1 and soluble E-selectin are associated with micro- and macrovascular complications in Type 1 diabetic patients. J Diabetes Complications. 2006; 20(3):188-95. DOI: 10.1016/j.jdiacomp.2005.06.005. View

16.

Richards P, Nowell M, Horiuchi S, McLoughlin R, Fielding C, Grau S . Functional characterization of a soluble gp130 isoform and its therapeutic capacity in an experimental model of inflammatory arthritis. Arthritis Rheum. 2006; 54(5):1662-72. DOI: 10.1002/art.21818. View

17.

Gabay C . Interleukin-6 and chronic inflammation. Arthritis Res Ther. 2006; 8 Suppl 2:S3. PMC: 3226076. DOI: 10.1186/ar1917. View

18.

Mitsuyama K, Matsumoto S, Rose-John S, Suzuki A, Hara T, Tomiyasu N . STAT3 activation via interleukin 6 trans-signalling contributes to ileitis in SAMP1/Yit mice. Gut. 2006; 55(9):1263-9. PMC: 1860050. DOI: 10.1136/gut.2005.079343. View

19.

Videm V, Albrigtsen M . Soluble ICAM-1 and VCAM-1 as markers of endothelial activation. Scand J Immunol. 2008; 67(5):523-31. DOI: 10.1111/j.1365-3083.2008.02029.x. View

20.

Nagaoka T, Kuo L, Ren Y, Yoshida A, Hein T . C-reactive protein inhibits endothelium-dependent nitric oxide-mediated dilation of retinal arterioles via enhanced superoxide production. Invest Ophthalmol Vis Sci. 2008; 49(5):2053-60. DOI: 10.1167/iovs.07-1387. View