Administration of gammalinolenic acid (GLA), an unsaturated fatty acid, reduces joint inflammation in patients with rheumatoid arthritis. Addition of GLA in vitro suppresses release of IL-1beta from human monocytes stimulated with LPS. LPS-induced IL-1beta release is followed by IL-1-induced IL-1beta release, an amplification process termed autoinduction. We show here with peripheral blood monocytes from normal volunteers and from patients with rheumatoid arthritis by using IL-1R antagonist to block autoinduction and IL-1alpha stimulation to simulate autoinduction that approximately 40% of IL-1beta released from LPS-stimulated cells is attributable to autoinduction and that GLA reduces autoinduction of IL-1beta while leaving the initial IL-1beta response to LPS intact. Experiments with cells in which transcription and protein synthesis were blocked suggest that GLA induces a protein that reduces pro-IL-1beta mRNA stability. IL-1beta is important to host defense, but the amplification mechanism may be excessive in genetically predisposed patients. Thus, reduction of IL-1beta autoinduction may be protective in some patients with endotoxic shock and with diseases characterized by chronic inflammation.

Post-trauma elevation of tumor necrosis factor alpha (TNF-alpha) appears to be critical in mediating many symptoms of systemic inflammatory response syndrome (SIRS), resulting in late mortality. Although increased monocyte (mphi) TNF-alpha production plays a pivotal role in this TNF-alpha elevation, the molecular mechanisms leading to increased mphi TNF-alpha production have yet to be elucidated. We demonstrate that, although TNF-alpha mRNA levels are increased in all trauma patients' mphi, which produce elevated levels of TNF-alpha protein, in the majority of patients, these increased TNF-alpha mRNA levels are under normal transcriptional and posttranscriptional control. Consequently, the increased TNF-alpha production by these patients' mphi is probably due to preactivation of these mphi by trauma-released mediators. However, a small minority of patients, whose mortality rate was 57%, produce TNF-alpha of primarily the membrane-associated type. The mphi TNF-alpha mRNA accumulation of these patients in response to in vitro stimulation is significantly augmented. All of these patients experienced SIRS. In this subset of patients' mphi, TNF-alpha mRNA stability was aberrantly increased. Such an increase in TNF-alpha mRNA stability could lead to devastatingly prolonged production of TNF-alpha protein. This demonstration of increased TNF-alpha mRNA stability in post-trauma mphi represents a novel correlation of elevated membrane-associated TNF-alpha protein, increased mortality, and a mechanism for this occurrence.