Apoptosis of cells must be regulated both positively and negatively in response to a variety of stimuli in the body. Various environmental stresses are known to initiate apoptosis via differential signal transduction cascades. However, induction of signals that may inhibit apoptosis is poorly understood, although a number of intracellular molecules that mediate inhibition of apoptosis have been identified. Here we present a novel murine macrophage-specific 54-kD secreted protein which inhibits apoptosis (termed AIM, for apoptosis inhibitor expressed by macrophages). AIM belongs to the macrophage scavenger receptor cysteine-rich domain superfamily (SRCR-SF), members of which share a highly homologous conserved cysteine-rich domain. In AIM-deficient mice, the thymocyte numbers were diminished to half those in wild-type mice, and CD4/CD8 double-positive (DP) thymocytes were strikingly more susceptible to apoptosis induced by both dexamethasone and irradiation in vivo. Recombinant AIM protein significantly inhibited cell death of DP thymocytes in response to a variety of stimuli in vitro. These results indicate that in the thymus, AIM functions in trans to induce resistance to apoptosis within DP cells, and thus supports the viability of DP thymocytes before thymic selection.
B cells undergo a complex series of maturation and selection steps in the bone marrow and spleen during differentiation into mature immune effector cells. The tumor necrosis factor (TNF) family member B cell activating factor of the TNF family (BAFF) (BLyS/TALL-1) plays an important role in B cell homeostasis. BAFF and its close homologue a proliferation-inducing ligand (APRIL) have both been shown to interact with at least two receptors, B cell maturation antigen (BCMA) and transmembrane activator and cyclophilin ligand interactor (TACI), however their relative contribution in transducing BAFF signals in vivo remains unclear. To functionally inactivate both BAFF and APRIL, mice transgenic for a soluble form of TACI were generated. They display a developmental block of B cell maturation in the periphery, leading to a severe depletion of marginal zone and follicular B2 B cells, but not of peritoneal B1 B cells. In contrast, mice transgenic for a soluble form of BCMA, which binds APRIL, have no detectable B cell phenotype. This demonstrates a crucial role for BAFF in B cell maturation and strongly suggests that it signals via a BCMA-independent pathway and in an APRIL-dispensable way.
Dichloromethylene diphosphonate (MDPCl2) encapsulated in multilamellar liposomes was selectively incorporated by macrophages, immediately transferred to lysosomes, then released from liposomes into lysosomes by enzymatic digestion of the liposomal lipid layers. From 4 h after ingesting liposome-encapsulated MDPCL2 murine macrophages in vivo and in vitro acquired the ultrastructural features of apoptosis, such as condensed nuclear chromatic, nuclear fragmentation, cell shrinkage, and blebbing of the plasma membrane. Murine peritoneal macrophages and isolated rat Kupffer cells incubated in the medium containing liposome-encapsulated MDPCl2 increased DNA fragmentation in a dose-dependent manner. Electrophoretic analysis of extracted DNA from the isolated Kupffer cells showed DNA fragmentation. Another diphosphonate, Alendronate (4-amino-1-hydroxy-butylidene-1,1-diphosphonate) had less potent macrophage cytotoxicity. However, MDPCl2, Alendronate, and gadolinium chloride in solution were not cytotoxic to macrophages. These results implied that the intralysosomal accumulation of MDPCl2 generates signals to induce macrophage apoptosis.
Depletion of mouse Kupffer cells and splenic macrophages following intravenous administration of liposome-entrapped clodronate severely reduced host resistance to primary infection with Listeria monocytogenes. Infection of clodronate-treated mice with a sublethal dose of L. monocytogenes resulted in death of the mice within 3 days. The macrophage depletion resulted in marked increases in bacterial growth in the liver and spleen, but not in other tissues. The proliferation of L. monocytogenes was observed in a large number of hepatocytes that underwent apoptosis. Infiltration of neutrophils in the liver and rapid formation of microabscesses were observed in the control mice after L. monocytogenes infection. However, there was less accumulation of neutrophils in the liver of Kupffer cell-depleted mice than in the control mice. Expression of macrophage inflammatory protein-2 (MIP-2) was enhanced in the livers of both the control and Kupffer cell-depleted mice after L. monocytogenes infection. MIP-2 was also induced in a murine hepatocyte cell line following L. monocytogenes infection. The administration of neutralizing anti-interleukin-8 receptor homolog antibody severely abrogated neutrophil infiltration into the Listeria-infected mouse liver. Anti-MIP-2 antibody moderately reduced neutrophil infiltration and microabscess formation in the liver. These findings indicate that Kupffer cells protect hepatocytes from L. monocytogenes infection and the resultant apoptosis. Moreover, MIP-2 and its related molecules produced by the infected hepatocytes regulate neutrophil infiltration and microabscess formation in primary listeriosis.
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