Thrombospondin 1 Is an Autocrine Negative Regulator of Human Dendritic Cell Activation

Abstract

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) β, 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) α, thereby eliciting protective and inflammatory immune responses. Microbial stimuli increase TSP production, which is further enhanced by IL-10 or TGF-β. The endogenous TSP produced during early DC activation negatively regulates IL-12, TNF-α, 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.

Modulation of murine dendritic cell function by adenine nucleotides and adenosine: Involvement of the A2B receptor

“…A microarray analysis of ATPcS-stimulated human monocytederived DC has revealed inter alia the striking up-regulation of two genes that could play a role in tolerance: TSP-1 and IDO [11]. TSP-1 can inhibit CD4 + Tcell proliferation, inhibit IL-12 production by DC [40] and activate TGF-b [41]. IDO inhibits the proliferation of CD4 + T cells by decreasing the concentration of tryptophan and/or via the generation of kynurenines [42].…”

The immune system and cardiac repair

“…Second, reduced angiogenesis may prevent extension of the inflammatory reaction. Third, direct antiinflammatory actions of the TSP-1 molecule, mediated through CD47 [333], may suppress the inflammatory response.…”

Immunocamouflage of latex surfaces by grafted methoxypoly(ethylene glycol) (mPEG): Proteomic analysis of plasma protein adsorption

“…The binding of beta-2-glycoprotein I precursor and thrombospondin could potentially serve beneficial functions in cell and tissue transplantation. Beta-2-glycoprotein binds to negatively charged phospholipids and inhibits the coagulation cascade [30,31], while thrombospondin-1 is a potent inhibitor of T-cell and dendritic cell activation [32,33].…”