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¹ Immunoregulation, Centre Hospitalier de l'Université de Montréal Research Center, Hospital Notre-Dame, Montreal, Quebec H2L 4M1,Canada
² Allergy Laboratories, Centre Hospitalier de l'Université de Montréal Research Center, Hospital Notre-Dame, Montreal, Quebec H2L 4M1,Canada
³ Department of Allergy and Immunology, National Research Institute for Child Health and Development
⁴ Laboratory for Allergy Transcriptome, Institute for Physical and Chemical Research, Research Center for Allergy and Immunology, Setagaya-ku, Tokyo 154-8567, Japan

Address correspondence to Marika Sarfati, Immunoregulation Laboratory, Centre Hospitalier de l'Université de Montréal Research Center, Hospital Notre-Dame (Pavillon Mailloux M4211K),1560 Sherbrooke Street East, Montreal, Quebec H2L 4M1, Canada. Phone: (514) 890-8000; Fax: (514) 412-7652; email: m.sarfati{at}umontreal.ca

Thrombospondin 1 (TSP) elicits potent antiinflammatory activities in vivo, as evidenced by persistent, multiorgan inflammation in TSP null mice. Herein, we report that DCs represent an abundant source of TSP at steady state and during activation. Human monocyte-derived immature dendritic cells (iDCs) spontaneously produce TSP, which is strongly enhanced by PGE₂ and to a lesser extent by transforming growth factor (TGF) ß, two soluble mediators secreted by macrophages after engulfment of damaged tissues. Shortly after activation via danger signals, DCs transiently produce interleukin (IL) 12 and tumor necrosis factor (TNF) , thereby eliciting protective and inflammatory immune responses. Microbial stimuli increase TSP production, which is further enhanced by IL-10 or TGF-ß. The endogenous TSP produced during early DC activation negatively regulates IL-12, TNF-, and IL-10 release through its interactions with CD47 and CD36. After prolonged activation, DCs extinguish their cytokine synthesis and become refractory to subsequent stimulation, thereby favoring the return to steady state. Such "exhausted" DCs continue to release TSP but not IL-10. Disrupting TSP–CD47 interactions during their restimulation restores their cytokine production. We conclude that DC-derived TSP serves as a previously unappreciated negative regulator contributing to arrest of cytokine production, further supporting its fundamental role in vivo in the active resolution of inflammation and maintenance of steady state.

Key Words: PGE₂ • TGF-ß • IL-12 • CD47 • CD36

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