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 Blood, 23 July 2009, Vol. 114, No. 4, pp. 796-806.
Prepublished online as a Blood First Edition Paper on May 22, 2009; DOI 10.1182/blood-2009-01-199406.

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IMMUNOBIOLOGY

CC chemokine ligand 2 down-modulation by selected Toll-like receptor agonist combinations contributes to T helper 1 polarization in human dendritic cells

Manuela Del Cornò1,*, Alessandro Michienzi1,*, Andrea Masotti2, Letizia Da Sacco2, Gian Franco Bottazzo2, Filippo Belardelli1, and Sandra Gessani1

1 Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, Rome; and 2 Laboratory of Gene Expression–Microarrays, Children's Hospital Bambino Gesù, Rome, Italy

Toll-like receptor (TLR) signaling activation by pathogens is critical to the induction of immune responses, and demands tight regulation. We describe in this study that CC chemokine ligand 2 (CCL2) secretion triggered by TLR4 or TLR8 engagement is strongly inhibited upon simultaneous activation of both TLRs in human monocyte-derived dendritic cells (DCs). Impaired CCL2 secretion occurs concomitantly to interleukin-12 up-regulation, being part of a complex regulatory circuit ensuring optimal T helper type 1 polarization. Interestingly, triggering selected TLRs or their combinations differently affects nuclear factor-{kappa}B p65 activation and microRNA expression. Overall, these results indicate that CCL2 supplies an important immunomodulatory role to DCs, and may contribute to dictate the cytokine profile in T helper type 1 responses induced by DCs.


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