Lipopolysaccharide desensitizes monocytes-macrophages to CD40 ligand stimulation.
Polymicrobial sepsis induces the suppression of macrophage function as determined by a reduction of pro-inflammatory cytokine production upon re-exposure to lipopolysaccharide (LPS) in vitro. Here, we examined whether macrophages were refractory to only LPS or if they were unable to respond to other stimuli such as CD40 ligand (CD40L). Monocytic cells exposed in vitro to LPS showed a dose-dependent reduction of their ability to produce interleukin-12 and tumour necrosis factor-alpha upon subsequent CD40L stimulation, as compared to cells stimulated with CD40L alone. Similarly, LPS interfered with the up-regulation of CD40, CD80 and CD86 induced by CD40L in monocytic cells. The effect of LPS on the response of monocytes to CD40L was similar whether these cells were directly exposed to LPS or cocultured with LPS-pretreated cells, indicating that soluble factors released by LPS stimulation could mediate tolerance to CD40L. We also show that the functional alterations induced by LPS in monocytes can be reversed by indomethacin, thus suggesting a role for inducible cyclooxygenase in mediating the LPS-induced hyporesponsive state of monocytes to CD40L. In conclusion, we propose that in vitro CD40L tolerance may be an appropriate model of monocyte alteration observed during septic immunosuppression and may help in the development of novel therapeutic strategies.
Sinistro
Anna
A
Department of Public Health and Cellular Biology, Chair of Infectious Diseases, University of Rome 'Tor Vergata', Rome, Italy.
Ciaprini
Chiara
C
Natoli
Silvia
S
Sussarello
Emanuele
E
Carducci
Francesca Calò
FC
Almerighi
Cristiana
C
Capozzi
Marcella
M
Bolacchi
Francesca
F
Rocchi
Giovanni
G
Bergamini
Alberto
A
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D018122:B7-1 Antigen / Q000378:metabolism; D051940:B7-2 Antigen / Q000378:metabolism; D019013:CD40 Antigens / Q000378:metabolism; D023201:CD40 Ligand / Q000276:immunology*; D002478:Cells, Cultured; D018920:Coculture Techniques; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004306:Dose-Response Relationship, Immunologic; D006801:Humans; D007108:Immune Tolerance / Q000187:drug effects; D007213:Indomethacin / Q000494:pharmacology; D018664:Interleukin-12 / Q000096:biosynthesis; D008070:Lipopolysaccharides / Q000276:immunology*; D009000:Monocytes / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D000894:Anti-Inflammatory Agents, Non-Steroidal; D018122:B7-1 Antigen; D051940:B7-2 Antigen; D019013:CD40 Antigens; D016861:Cyclooxygenase Inhibitors; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D023201:CD40 Ligand; D018664:Interleukin-12; D007213:Indomethacin