Interaction with autologous platelets multiplies interleukin-1 and tumor necrosis factor production in mononuclear cells.

The effect of activated platelets on cytokine production by human peripheral blood mononuclear cells (PBMC) was investigated. When PBMC were coincubated with activated autologous platelets amid lipopolysaccharide (LPS, 50-100 pg/mL) for 8 h, the production of interleukin (IL)-1alpha increased 11- to 18-fold and tumor necrosis factor (TNF)-alpha 3- to 5-fold compared with PBMC without platelets. Activated platelets in a dual-chamber well that prevented platelet-PBMC contact but permitted passage of soluble factors enhanced IL-1alpha production (P < .01). Platelet-PBMC contact in the chamber resulted in a further enhancement of IL-1alpha production. These data suggest that platelet-PBMC interaction, both directly and with platelet-derived factors, enhances production of shock-producing IL-1alpha and TNF-alpha, albeit differently. The interaction of platelets with monocytes may play an important role in the pathophysiology of sepsis and disseminated intravascular coagulation.

A new biologic role for C3a and C3a desArg: regulation of TNF-alpha and IL-1 beta synthesis.

The complement activation products C3a and C3a desArg are generated in the course of trauma, infection, tissue injury, and ischemia. We have investigated the effects of C3a and C3a desArg on gene expression and protein synthesis of TNF-alpha and IL-1 beta in PBMC. Neither C3a nor C3a desArg alone induced detectable protein or mRNA levels for TNF-alpha and IL-1 beta. C3a modulated LPS-induced TNF-alpha and IL-1 beta synthesis. In nonadherent PBMC, C3a suppressed LPS-induced synthesis of TNF-alpha (20-71% decrease by 0.2-10 microgram/ml of C3a, p less than 0.01) and IL-1 beta (19-57% decrease by 0.5-10 microgram/ml of C3a, p less than 0.01), independently of endogenous production of PGE2. C3a also suppressed LPS-induced mRNA levels for TNF-alpha and IL-1 beta. In contrast, in adherent PBMC, C3a at 5 to 20 microgram/ml enhanced LPS-induced TNF-alpha (75-188% increase, p less than 0.001) and IL-1 beta (119-274% increase, p less than 0.001) synthesis. C3a enhanced TNF-alpha and IL-1 beta mRNA levels in LPS-stimulated adherent cells. Furthermore, C3a desArg shared with C3a the ability to modulate LPS-induced mRNA and protein synthesis for TNF-alpha and IL-1 beta. These results suggest that C3a, thought to be proinflammatory, and C3a desArg, thought to be biologically inactive, are modulators of inflammation. Both C3a and C3a desArg may enhance cytokine synthesis by adherent monocytes at local inflammatory sites, while inhibiting the systemic synthesis of proinflammatory cytokines by circulating cells.

Coagulation of whole blood stimulates interleukin-1 beta gene expression.

To study interleukin (IL)-1 beta gene expression, reverse transcription-polymerase chain reaction was used on 25-microL whole blood samples from 11 healthy subjects. Coagulated and unclotted whole blood was compared. There was no evidence of IL-1 beta gene expression in any time zero samples (i.e., whole blood from which mRNA was immediately extracted) from 11 subjects, whereas a 388-bp band representing IL-1 beta mRNA was detected in all coagulated samples. No mRNA for IL-1 beta was detected in EDTA-anticoagulated whole blood, although in these samples the addition of lipopolysaccharide as a positive control induced the expression of IL-1 beta. In time course studies on samples allowed to clot, mRNA for IL-1 beta was detectable after 30 min. These findings demonstrate that IL-1 beta gene expression is not present in circulating cells of healthy subjects and that coagulation is a stimulus for IL-1 beta gene expression. This may be a mechanism by which thrombosis produces inflammation and fever.

Cytokine-processing enzymes. Stopping the cuts.

The recently discovered enzymes that process the precursors of inflammatory cytokines are good targets for the design of new anti-inflammatory therapeutic agents.