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

Krzysztof Laudanski, Asit De, Sabine Brouxhon, Stephanos Kyrkanides, Carol Miller-Graziano

Research output: Contribution to journalArticlepeer-review

14 Scopus citations


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.

Original languageEnglish
Pages (from-to)204-212
Number of pages9
Issue number3
StatePublished - Sep 2004


  • Antigen-presenting cell function
  • CD64
  • EP receptors
  • PGE insensitivity
  • Toll-like receptors

ASJC Scopus subject areas

  • Emergency Medicine
  • Critical Care and Intensive Care Medicine


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