Interleukin-6: a potential target for post-thrombotic syndrome.
BACKGROUND
Deep vein thrombosis (DVT) and its associated sequelae, post-thrombotic syndrome (PTS), are significant health care problems in the United States. It is estimated that a maximum of 60% of patients diagnosed with DVT develop PTS, which is characterized by extensive perivenous and mural fibrosis. Interleukin-6 (IL-6) has been linked to fibrosis, and high circulating plasma levels have been found to increase the risk of developing DVT. The aim of this study was to elucidate the role of IL-6 in the progression of vein wall fibrosis by using a mouse model of DVT.


RESULTS
C57BL/6 mice (n = 136) were treated with either anti-IL-6 monoclonal antibody or control rat-immunoglobulin G. Thrombus was induced by using an inferior vena cava ligation model. The inferior vena cava and thrombus were harvested at days 2, 6, or 14 for thrombus weight, gene expression of IL-6 and/or C-C motif chemokine ligand 2 (CCL2), inflammatory cell recruitment, and morphometric analysis of vein wall fibrosis. Mice treated with anti-IL-6 had smaller thrombus weights at day 2, decreased vein wall gene expression and protein concentration of CCL2 at day 2, and impaired vein wall influx of monocytes from days 2 to 6, as compared with controls. Intimal thickness was reduced by 44% (p < 0.05) and vein wall collagen deposition was decreased by 30% at day 14 in the anti-IL-6 group (p < 0.05).


CONCLUSIONS
Neutralizing IL-6 throughout venous thrombogenesis decreased the production of CCL2, reduced monocyte recruitment, and decreased vein wall intimal thickness and fibrosis. These results suggest that IL-6 may serve as a therapeutic target to prevent the fibrotic complications seen in PTS.
Section of Vascular Surgery, Department of Surgery, University of Michigan, Ann Arbor, MI, USA.
Brandon M
BM
Wojcik
Shirley K
SK
Wrobleski
Angela E
AE
Hawley
Thomas W
TW
Wakefield
Daniel D
DD
Myers
Jose A
JA
Diaz
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D003094:Collagen / Q000378:metabolism; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005355:Fibrosis; D007150:Immunohistochemistry; D015850:Interleukin-6 / Q000097:blood / Q000235:genetics / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000187:drug effects / Q000276:immunology; D054070:Postthrombotic Syndrome / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D012333:RNA, Messenger / Q000378:metabolism; D013997:Time Factors; D017539:Tunica Intima / Q000187:drug effects / Q000276:immunology; D015854:Up-Regulation; D014682:Vena Cava, Inferior / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D020246:Venous Thrombosis / Q000150:complications / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology
D000911:Antibodies, Monoclonal; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D015850:Interleukin-6; D012333:RNA, Messenger; D003094:Collagen