HETEs enhance IL-1-mediated COX-2 expression via augmentation of message stability in human colonic myofibroblasts

Abstract

Proinflammatory cytokines and eicosanoids are central players in intestinal inflammation. IL-1, a key cytokine associated with intestinal mucosal inflammation, induces COX-2 expression in human colonic myofibroblasts (CMF) and increased prostaglandin E(2) secretion is associated with inflammatory bowel disease (IBD) and colorectal cancer (CRC). We have previously demonstrated that IL-1alpha-induced cyclooxygenase-2 (COX-2) expression is the result of NF-kappaB- and ERK-mediated transcription, as well as COX-2 message stabilization, which depends on p38, MAPKAPK-2 (MK-2) and human antigen R (HuR) RNA binding protein activation. Lipoxygenase (LOX)-derived hydroxyeicosatetraenoic acids (HETEs) are elevated in IBD and colonic adenomas and "cross talk" has been observed between the COX and LOX pathways. Since COX-2 expression is primarily in CMFs in colonic adenomas, we examined the impact of LOX metabolites, particularly HETEs, on IL-1alpha-induced COX-2 expression in human CMFs. Although 5(S)-, 12(R)-, and 15(S)-HETEs alone had little to no effect on COX-2 expression, they enhanced IL-1-mediated COX-2 expression 3.6 +/- 0.5-fold. Studies utilizing heterogeneous nuclear RNA amplification and 5,6-dichloro-beta-d-ribofuranosylbenzimidazole treatment were undertaken to measure COX-2 transcription and message stabilization, respectively. We found that HETEs enhanced IL-1-induced COX-2 mRNA levels in CMF as the result of increased p38, MK-2, and HuR activity, increasing message stability greater than that observed with IL-1 alone. Thus HETEs can act synergistically with IL-1alpha to induce COX-2 expression in human CMFs. HETEs may play a role in both colonic inflammation and in increasing the risk of CRC in IBD independently and via induction of COX-2-mediated prostaglandin secretion.

Lenalidomide treatment promotes CD154 expression on CLL cells and enhances production of antibodies by normal B cells through a PI3-kinase–dependent pathway

“…47 Studies examining the ability of lenalidomide or related drugs to stabilize RNA are limited, although in colon cancer cell lines, thalidomide has been shown to diminish COX2 mRNA stability via shuttling of HuR. 48 Further study of the mechanism of CD154 mRNA stabilization by lenalidomide in CLL and the kinetics of this process warrant further study that is ongoing.…”

D-4F-mediated reduction in metabolites of arachidonic and linoleic acids in the small intestine is associated with decreased inflammation in low-density lipoprotein receptor-null mice

“…For example, it is not possible to determine from these studies whether the reduction in free metabolites of arachidonic and linoleic acids occurred because of a reduction in substrate (e.g., free arachidonic acid), a decrease in lipoxygenase and cyclooxygenase activities, or a reduction in the activities of other enzyme pathways or whether the decrease resulted from the binding and removal of the final stable products of these pathways. It has been reported that the latter can interact to enhance the former ( 12,13 ), making the distinction diffi cult to determine. These many possibilities need to be addressed by future studies.…”

Mitogen activated protein kinases: a role in inflammatory bowel disease?

“…These studies have investigated various cell types (both primary and cultured), including monocytes, colonocytes and myofibroblasts, but also include a host of animal studies where IBD-like inflammation was induced. Through the signalling pathways outlined previously, inflammatory responsesmainly cytokine production and inflammatory cell infiltration -have been shown to be attenuated by usage of specific inhibitors against p38 and JNK [27,35,38,44,52,63].…”