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Gema Tarrasón,
Mariona Aulí,
Sanam Mustafa,
Vladislav Dolgachev,
Maria Teresa Domènech,
Neus Prats,
María Domínguez,
Rosa López,
Nuria Aguilar,
Marta Calbet,
Mercè Pont,
Graeme Milligan, Steven L Kunkel,
Nuria Godessart
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ABSTRACT: Agonists of the sphingosine-1-phosphate (S1P) receptors, like fingolimod (FTY720), are a novel class of immunomodulators. Administration of these compounds prevents the egress of lymphocytes from primary and secondary lymphoid organs causing peripheral blood lymphopenia. Although it is well established that lymphopenia is mediated by S1P receptor type 1 (S1P1), the exact mechanism is still controversial. The most favored hypothesis states that S1P1 agonists cause internalization and loss of the cell surface receptor on lymphocytes, preventing them to respond to S1P. Hence, S1P1 agonists would behave in vivo as functional antagonists of the receptor. For this hypothesis to be valid, a true S1P1 antagonist should also induce lymphopenia. However, it has been reported that S1P1 antagonists fail to show this effect, arguing against the concept. Our study demonstrates that a S1P1 antagonist, W146, induces a significant but transient blood lymphopenia in mice and a parallel increase in CD4+ and CD8+ lymphocytes in lymph nodes. Treatment with W146 also causes the accumulation of mature T cells in the medulla of the thymus and moreover, it induces lung edema. We show that both the S1P1 antagonist and a S1P1 agonist cause lymphopenia in vivo in spite of their different effects on receptor expression in vitro. Although the antagonist purely blocks the receptor and the agonist causes its disappearance from the cell surface, the response to the endogenous ligand is prevented in both cases. Our results support the hypothesis that lymphopenia evoked by S1P1 agonists is due to functional antagonism of S1P1 in lymphocytes.
International immunopharmacology 07/2011; 11(11):1773-9. · 2.21 Impact Factor
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ABSTRACT: Leukocyte recruitment, accumulation, and activation have been both a unifying and enigmatic feature of a variety of autoimmune pathologies. While these processes were not well-known for decades, recent scientific discoveries have underscored the importance of specific chemokines in the evolution of autoimmunity. This has been supported by in vivo data from clinical studies and animal model experiments. Although chemokines are an attractive target for drug development, there are hurdles that need to be cleared. Nonetheless, the quest to understand chemokine biology and develop effective therapies continues to capture the imagination of scientists in academia and pharma alike.
Autoimmunity Reviews 01/2003; 1(6):313-20. · 6.62 Impact Factor
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ABSTRACT: The mechanistic relationships between initiating stimulus, cellular source and sequence of chemokine expression, and leukocyte recruitment during inflammation are not clear. To study these relationships in an acute inflammatory process, we challenged a murine air pouch with carrageenan. A time-dependent increase in TNF-alpha, monocyte chemottractant protein-1 (MCP-1), macrophage-inflammatory protein-1alpha (MIP-1alpha), RANTES, KC, and MIP-2 was found in the exudates preceding cell recruitment, but displaying different kinetic profiles. Air pouches generated for 2, 6, or 9 days before initiating inflammation demonstrated a proportional increase in the number of cells lining the cavities. Two hours after carrageenan stimulation, the synthesis of TNF-alpha and all chemokines but RANTES increased in proportion to the lining cellularity, although no differences in infiltrating leukocytes were found, suggesting that the early source of these mediators is resident cells. To assess the contribution of neutrophils to chemokine synthesis at later time points, we used neutropenic animals. Neutrophil depletion caused a decrease in TNF-alpha (51%), KC (37%), MIP-1alpha (30%), and RANTES (57%) levels and a 2-fold increase in monocytes 4 h after challenge. No effect on MIP-2 and MCP-1 levels was observed. The selective blockade of CXCR2 or CCR1 inhibited neutrophil recruitment by 74% and 54%, respectively, without a significant inhibition of monocytes. A differential effect on TNF-alpha and MCP-1 levels was observed after these treatments, indicating that the two receptors did not subserve a mere redundant chemotactic role. Overall, our results suggest that chemokines synthesized by resident cells play an important role in the evolution of the inflammatory response.
The Journal of Immunology 01/2003; 169(11):6467-73. · 5.79 Impact Factor
