Effect of prostaglandin E2 on PMA-induced macrophage differentiation
Introduction
Trauma that induce a large volume of tissue injury and hypovolemic hemorrhagic shock such as burns, severe fractures and extensive surgical procedures, could result in severe impairment of immunologic reactivity that in turn leads to the development of serious infections [1]. A sequence of states of cellular activation has been described in the aftermath of trauma and, to a certain degree, they can also be associated with consecutive clinical states such as the acute phase response, anergy, infection, and organ failure [2]. The monocyte/macrophage lineage plays a key role in this immunological derangement as macrophage participates to a number of regulatory loops with T cells [2]. In fact, under stressful conditions macrophage show an immediate hyperactivation characterized by an excessive release of proinflammatory cytokines [3] and prostaglandin E2 (PGE2), the most powerful endogenous immune suppressant [4], [5], followed by a paralysis of cell functions, which is then overcome in few days with the recruitment of immature macrophage [6].
While the role of PGE2 in the after trauma impairment of the immune response has been extensively studied [7], [8], [9], [10], its possible role in the accelerated macrophage differentiation remains elusive [11], [12].
Human HL-60 myeloid leukemia cells retains the ability to differentiate along the monocyte, macrophage, or granulocyte pathway [13] in response to a wide variety of differentiation inducers and this cell line is a suitable model to study the modulation of macrophage differentiation.
In fact, the phorbol 12-myristate 13-acetate (PMA) induces HL-60 terminal differentiation toward the macrophage lineage [14], [15] characterized by the appearance of cell adhesion and spreading [16], [17], matrix metalloproteinase-9 (MMP-9) [17], [18], [19] and tumor necrosis factor-α (TNF-α) production [18], [19]. The present study was initiated to investigate the effect of PGE2 on the cell adhesion, MMP-9 and TNF-α production in untreated and PMA-treated HL-60 cells in order to clarify if PGE2 could participate in the onset of accelerated macrophage differentiation observed in the patients victims of major trauma.
Section snippets
Materials
The PKC activator phorbol 12-myristate 13-acetate (PMA), prostaglandin E2 (PGE2), forskolin and all the material for cell culture and substrate zymography were obtained from Sigma (St. Louis, MO, USA). Sulprostone, Misoprostol, Butaprost and 16,16-dimethyl PGE2 were purchased from Cayman Chemical (Ann Arbor, MI, USA). The MAP kinase kinase inhibitor PD 98,059 (PD), the PI-3K inhibitor Wortmannin (WRT), the inhibitor of adenilyl cyclase SQ 22,536 (SQ) and the Adenosine 3′,5′-cyclic
PGE2 increases the PMA-induced macrophage differentiation in HL-60 via a TNF-α independent pathway
The macrophage differentiation of HL-60 cells was monitored measuring the number of adherent cells and the activity of the MMP-9 (gelatinase B) in the cell medium for 24 h. The addition of PGE2 (1 μM) to the HL-60 cell in the presence of 10% FCS (Fig. 1B) did not altered significantly the spontaneous cell adhesion that occurs also in the undifferentiated HL-60 cells (Fig. 1A). In fact the mean adherent cell number ± standard error (S.E.) scored in 10 random fields was 81 ± 3 for in the control
Acknowledgements
The authors thank Dr. M. De Andrea from the Microbiology Laboratory, for the kind gift of HL-60 cells, Dr. C. Campa and Dr. D. Speretta from the Human Anatomy Laboratory, for the precious and skillful technical assistance.
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