3 and MMP13. For IL 6, we observed a slight increase at the lowest concentrations, but a decrease at higher concentrations. This may be due to biphasic effects of curcumin that are based on its dual function to either scavenge or produce reactive o ygen species. However, the biphasic nature of curcumin cannot e plain that higher concentrations of curcumin strongly stimulated e pression of TNF in human intervertebral disc cells, which is different from what is described in the literature. Based on the current study we do not know showed that curcumin inhibits phosphorylation and degradation of I��B and thus translocation of the p65 subunit of NF ��B to the nucleus, indicating that inhibition of the NF ��B pathway takes place at a step before I��B phosphorylation.

In intestinal epithelial cells, curcumin seems to e ert its effects by blocking a sig nal leading to IKK activity. How ever, in our e perimental setting, curcumin did not seem Batimastat to reduce IL 1B induced nuclear translocation of NF ��B p65 or NF ��B DNA binding, which is in contrast to data obtained by Yu et al. on interverte bral disc cells. Toll like receptors We were able to demonstrate a down regulation of TLR2 mRNA e pression after treating IL 1B prestimulated IVD cells with curcumin, which confirms findings in other cell types such as monocytic THP 1 cells, HL 60 pro myelocytic leukemia cells and primary peripheral blood polymorphonuclear neutrophils. However, in a leukemia cell line, Reuter et al. showed an increase in TLR2 due to curcumin, although most inflammatory mediators were simultaneously down regulated in this study.

There is also some evidence in the literature that curcumin can reduce e pression levels of TLR4. Based on how little is known about TLRs and curcumin so far, more research is needed to establish a causal relationship between therapeutic efficacy of curcu min and TLR2 activity. MAP kinases The mitogen activated protein kinase signaling pathways, including JNK, p38 and e tracellular signal regulated kinase, play an important role in the regulation of inflammatory responses. As MAP kinases are regulated by phosphorylation cascades, their activity can be determined by detecting phosphorylation levels. We found that curcumin was able to inhibit phos phorylation of JNK in IL 1B prestimulated IVD cells, which is similar to primary chondrocytes.

Import antly, pharmacological inhibition of JNK has previously been shown to suppress MMP1, MMP3 and MMP13 mRNA e pression in bovine and murine IVD cells. In contrast, phosphorylation of p38 and ERK was induced upon curcumin treatment in IL 1B prestimu lated IVD cells as well as in curcumin only treated IVD cells, with a synergistic effect of IL 1B and curcumin. It may be possible that activation of p38 and ERK led to the up regulation of TNF e pression which was observed when IL 1B pretreated and un treated IVD cells were e posed to curcumin, but our e perimental design does not allow to establish a causal relationship between MAP kin