Pro-inflammatory cytokine release by peripheral blood mononuclear cells from patients with advanced pancreatic cancer: relationship to acute phase response and survival.

The acute phase protein response (APPR) and peripheral blood mononuclear cell-derived inflammatory cytokine production was assessed in patients with advanced pancreatic cancer and age-matched healthy volunteers. We examined the relationship between the APPR, cytokine production and survival in these patients. Forty-two patients with pancreatic cancer cachexia and twelve age-matched healthy controls were recruited. The nutritional status, Karnofsky performance score, C reactive protein (CRP), serum interleukin-6, and in vitro monocyte interleukin-1 and interleukin-6 production were measured. The dates of death of the pancreatic cancer patients were subsequently obtained and appropriate patient variables at baseline were entered into a Cox's proportional hazards model. The cancer patients had significantly lower: body mass index, Karnofsky performance score, serum albumin and elevated CRP and stimulated interleukin-6 production. Both univariate and multivariate analysis demonstrated a strong association between tumour stage, CRP, stimulated interleukin-6 production and survival. Monocytes in cachectic pancreatic cancer patients are primed to produce high levels of interleukin-6 when stimulated. Overproduction of interleukin-6 has a negative impact on survival. Decreased survival is associated with an elevated APPR. While the elevated APPR is probably related to locally produced interleukin-6 in the liver, it seems possible that locally and systemically produced interleukin-6 influences survival.

The effects of macrophage migratory inhibitory factor on acute-phase protein production in primary human hepatocytes.

Macrophage inhibitory factor (MIF) is a pituitary peptide released during the physiological stress response, a T-cell product secreted during the antigen-specific response and a pro-inflammatory macrophage cytokine secreted after LPS stimulation. It has become apparent that MIF is central to the regulation of the inflammatory response and is implicated in the pathogenesis of a variety of acute and chronic inflammatory conditions. This is, at least in part, due to the apparent counter-regulation of the anti-inflammatory actions of glucocorticoids, including the reversal of glucocorticoid-mediated IL-6 release inhibition. This study examines the effect of recombinant MIF on regulation of the acute phase response in isolated human hepatocytes. MIF alone increased C-reactive protein (CRP) release in a dose-dependent manner < or = 0.1 ng/ml after which the effects of MIF were attenuated. In combination with IL-6 both CRP and and alpha-1-antichymotrypsin (ACT) release were increased above levels found with either IL-6 or MIF treatment alone. Dexamethasone attenuated the effects of MIF upon CRP production but increased the MIF stimulated release of ACT. The study demonstrates that the effects of MIF upon the acute phase response are complex and can differentially modulate the production of acute phase proteins depending on the presence of other factors.

Eicosapentaenoic acid perturbs signalling via the NFkappaB transcriptional pathway in pancreatic tumour cells.

In addition to various roles in membrane structure and metabolism, polyunsaturated fatty acids have effects on signal transduction and on the regulation of gene expression. Eicosapentaenoic acid (EPA) is an omega-3 fatty acid which is known to induce cell cycle arrest and apoptosis in pancreatic tumour cells. NFkappaB is a key transcription factor regulating genes involved in the immune response and has been implicated in apoptotic pathways. In this study we investigated the effect of eicosapentanoic acid on the NFkappaB pathway in pancreatic tumour cells. The pancreatic cell line MIA PaCa2 was incubated in the presence of the fatty acids EPA (n-3), arachidonic acid (AA, n-6) or oleic acid (OA, n-9) before pulsing with TNF to provide a kinetic assessment of NFkappaB activation and IkappaBalpha degradation. Pre-incubation of pancreatic cells with EPA or AA for 2 h before pulsing with TNF preserved IkappaBalpha but did not prevent NFkappaB activation. Indeed, NFkappaB activation was prolonged after exposure to EPA. N-acetyl-L-cysteine did not influence the effect of EPA on TNF-stimulated IkappaBalpha degradation. These results suggest that the omega-3 fatty acid EPA perturbs the NFkappaB pathway by a novel mechanism. This mechanism may be important in delineating alternative pathways to NFkappaB activation.