Relevance of IL-6 and MMP-9 to cerebral arteriovenous malformation and hemorrhage

The aim of the present study was to investigate the association of inflammatory cytokines and matrix metalloproteinase-9 (MMP-9) with cerebral arteriovenous malformation (AVM) and hemorrhage. A total of 31 AVM patients were divided into groups according to specimen sources; a ruptured group with 14 patients and an unruptured group with 17 patients. The control group comprised 30 epilepsy patients who underwent temporal lobectomy. Peripheral blood was obtained from the 30 control and all 31 AVM patients preoperatively. Tissue samples were removed from the AVM nidus during surgery or from the temporal lobes of patients undergoing surgical treatment for epilepsy. Enzyme-linked immunosorbent assay (ELISA) was used to measure plasma interleukin (IL)-6 levels. Western blot analysis was used to measure the levels of MMP-9 and transcription factors NF-kappa B and I kappa B alpha in the tissues. Immunofluorescence was used to measure tissue MMP-9 expression in each group. Gelatin zymography revealed the expression of activated MMP-2 and MMP-9 in the tissues. All the specimens were analyzed by routine hematoxylin and eosin (H& E) staining. IL-6 levels in the blood of the ruptured group were significantly higher compared with those of the unruptured and control groups (33.25+/-4.77 vs. 23.79+/-1.20, P<0.05; and 33.25+/-4.77 vs. 15.56+/-0.97, P<0.0001, respectively). NF-kappa B expression in the AVM ruptured group was significantly higher compared with that of the control group (5.00+/-0.12 vs. 2.36+/-0.33, P<0.05), but not with the unruptured group (5.00+/-0.12 vs. 2.96+/-0.69, P>0.05). The expression levels of I kappa B alpha in the ruptured and unruptured groups were similar to each other, but significantly less than those in the control group (0.12+/-0.02 vs. 1.27+/-0.06, P<0.001; and 0.45+/-0.15 vs. 1.27+/-0.06, P<0.01, respectively). MMP-9 protein expression levels in the unruptured group were increased compared with those in the control and ruptured groups (1.21+/-0.34 vs. 0.35+/-0.06, P<0.05; and 1.21+/-0.34 vs. 0.32+/-0.08, P<0.05, respectively). Gelatin zymography showed that the activity of MMP-9 was significantly higher in the ruptured compared with the unruptured and control groups (0.97+/-0.08 vs. 0.40+/-0.09, P<0.01; and 0.97+/-0.08 vs. 0.30+/-0.07, P<0.01, respectively). In the ruptured group, active MMP-2 expression levels were significantly higher compared with those in the other two groups (1.36+/-0.17 vs. 0.55+/-0.12, P=0.019; 1.36+/-0.17 vs. 0.36+/-0.09, P=0.006). The levels of IL-6 in the blood correlated with the tissue levels of activated MMP-9 (r=0.1691, P=0.0240). In conclusion, IL-6 expression levels were increased in the plasma of patients with cerebral AVM and this correlated with the activated MMP-9 levels of AVM tissues. Thus, plasma IL-6 levels are a potential predictor of hemorrhage risk in AVM patients.