Prostaglandins, a family of lipidic molecules released during inflammation, display immunomodulatory properties in several models. One use includes exposure of monocyte-derived dendritic cells (DCs) to a cocktail of cytokines that contains prostaglandin E 2 (PGE 2 ) for purposes of maturation; such cells are currently being used for cancer immunotherapy trials. Our analysis of the transcription profile of DCs matured in the presence of tumor necrosis factor ␣ (TNF␣) and PGE 2 revealed a strong up-regulation of indoleamine 2-3 dioxygenase (IDO), an enzyme involved in tryptophan catabolism and implicated in both maternal and T-cell tolerance. Using quantitative assays to monitor levels of IDO mRNA, protein expression, and enzyme activity, we report that PGE 2 induces mRNA expression of IDO; however, a second signal through TNF receptor (TNF- R IntroductionProstaglandin E 2 (PGE 2 ) is a catabolite of arachidonic acid and is generated by the sequential activity of cyclo-oxygenase (COX) and prostaglandin E synthase. 1 Produced during inflammation, PGE 2 is believed to act as a counter-inflammatory agent, modulating inflammatory responses and helping to restore tissue homeostasis. For example, PGE 2 has been reported to suppress T-cell proliferation, 2,3 inhibit macrophage and dendritic-cell cytokine production (eg, and tumor necrosis factor ␣ [TNF␣] 4,5 ), and modulate antigen presentation by down-regulating expression of major histocompatability complex (MHC) II. 6 Additionally, PGE 2 may skew CD4 ϩ T cells toward a T helper cell type 2 (T H 2) phenotype 7,8 and B cells toward immunoglobulin E (IgE) production. 5 In other studies, PGE 2 has been shown to play a role in T-cell development 9 and may be an inhibitor of apoptosis in doublepositive thymocytes. 10 Consistent with these reports, expression of various prostaglandin biosynthetic enzymes and receptors has been detected in the thymus. 11 Dendritic cells (DCs) are considered to be the only antigenpresenting cell (APC) capable of priming naive T cells, and they are also potent stimulators of recall responses. 12 Briefly, DCs exist in the periphery as immature cells where they serve as "sentinels," responsible for capturing antigen. Upon maturation, DCs migrate to the draining lymphoid organs, where they may initiate immune responses. This ability to traffic out of peripheral tissue with captured antigen and enter the afferent lymph is unique to the DCs, making them the appropriate carrier of tissue-restricted antigen to lymphoid organs for the initiation of immunity. 12 Their role in priming T cells has also prompted much interest in discovering strategies to efficiently use DCs carrying tumor antigen for adoptive transfer and immunization of tumor-reactive T cells. Our understanding of DC biology, however, has not resulted in overwhelming success; few DC-based studies have reported an effect greater than the 10% rate achieved by Coley. [13][14][15] Given that DCs are capable of mediating both T-cell priming as well as T-cell inactivation (tolerance), a deeper ...

Type I interferon (IFN-I) is constitutively produced in the bone marrow (BM), and induced at sites of inflammation and following infection by viruses or microorganisms. We have previously shown that IFN-I regulates the generation and selection of normal B cell populations in the BM. In the present work, we assess the effects of IFN-I on mature B cell function by monitoring the responses of IFN-alpha/beta-treated murine splenic B cells to apoptotic, mitogenic and activating stimuli. A similar analysis is performed on BM mature B cells obtained from wild-type or IFN-I receptor-deficient mice. IFN-alpha/beta is shown to induce B cells to a state of partial activation characterized by the up-regulation of CD69, CD86 and CD25 molecules in the absence of either proliferation or terminal differentiation. B cells treated with IFN-alpha/beta show an increased survival and resistance to Fas-mediated apoptosis. IFN-alpha/beta also enhances B cell responses to BCR ligation such as calcium fluxes, IgM internalization, induction of activation markers and proliferation. These results indicate that in addition to its inhibitory effect on viral replication and T cell apoptosis, IFN-alpha/beta plays an essential role during an inflammatory response by lowering the threshold for B cell induction, thereby promoting fast and polyclonal antibody responses.

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.