Abnormal PGE₂ regulation of monocyte TNF-α levels in trauma patients parallels development of a more macrophage-like phenotype

Some trauma patients' monocytes (MO) increase TNF-α levels concomitant to augmenting production of the TNF-α inhibitor prostaglandin E₂ (PGE₂), suggesting posttrauma MO insensitivity to PGE₂ effects. This study assesses additional posttrauma MO PGE ₂ insensitivity effects on altering TNF-α form (membrane versus secreted), down-regulating MO receptor expression, and depressing MO APC function. Posttrauma MO TNF-α insensitivity to exogenous and autocrine PGE₂ correlated to accumulation of TNF-α primarily as a membrane-bound cytokine (mTNF-α). MO retention of mTNF-α correlated with unfavorable clinical outcomes and loss of antigen-presenting cell (APC) function as assessed by depressed MLR and dendritic cell (DC) differentiation. MO TNF-α sensitivity to down-regulation by IL-10 was retained, suggesting that PGE₂-related functions are specifically altered in these patients' MO. Freshly isolated MO from all trauma patients had decreased expression of Toll-like receptor 4 (TLR4) for gram-negative bacteria. Exogenous PGE₂ at high (10^-6 M) or low (10^-8 M) concentrations decreased normals' and further decreased APC-competent patients' MO TLR4 expression but had no effect on TLR2. Patients' APC-dysfunctional MO failed to further down-regulate their TLR4 expression in response to additional PGE₂, demonstrating another form of PGE₂ insensitivity. One of the primary MO prostaglandin receptors, eicosanoid receptor 4 (EP4), was decreased on patients' APC dysfunctional MO, suggesting that depressed EP4 expression could contribute to PGE₂ insensitivity in patients' MO. The APC dysfunctional MO's dysregulation of TLR4 expression paralleled increased macrophage-like characteristics such as increased CD64 expression density, elevated mTNF-α production, and increased PGE₂ levels. Increased PGE₂ levels still decreased patients' MO APC functions but failed to depress either MO TLR4 expression or mTNF-α levels, suggesting differential involvement of EP receptors in postinjury PGE₂-mediated effects.