The Journal of Experimental Medicine
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© The Rockefeller University Press, 0022-1007/1999/1/413/ $5.00
The Journal of Experimental Medicine, Volume 189, Number 2, January 18, 1999 413-422

Articles

Increased Susceptibility of Thymocytes to Apoptosis in Mice Lacking AIM, a Novel Murine Macrophage-derived Soluble Factor Belonging to the Scavenger Receptor Cysteine-rich Domain Superfamily

Toru Miyazaki*, Yumiko Hirokami*, Nobuyuki Matsuhashi{ddagger}, Hisakazu Takatsuka§, and Makoto Naito§

From the * Basel Institute for Immunology, CH-4005 Basel, Switzerland; the {ddagger} Third Department of Internal Medicine, Faculty of Medicine, University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan; and the § Second Department of Pathology, Niigata University School of Medicine, Niigata 951-8510, Japan

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.

Key Words: apoptosis • scavenger receptor cysteine-rich • macrophage • inhibitory factor • knockout mouse

Address correspondence to Toru Miyazaki, The Basel Institute for Immunology, Grenzacherstrasse 487, postfach CH-4005, Basel, Switzerland. Phone: 41-61-605-1303; Fax: 41-61-605-1364; E-mail: miyazaki{at}bii.ch

The Basel Institute for Immunology was founded and is supported by F. Hoffman-La Roche Ltd. (Basel, Switzerland).

Abbreviations used: AIM, apoptosis inhibitor expressed by macrophages; B6, C57Bl/6; BrdU, bromodeoxyuridine; CHO, Chinese hamster ovary; DN, double negative; DP, double positive; ES, embryonic stem; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; PEC, peritoneal exudate cell; RAG, recombination activating gene; SRCR, scavenger receptor cysteine-rich; SRCR-SF, scavenger receptor cysteine-rich domain superfamily; SP, single positive; TdT, terminal deoxynucleotidyl transferase; TUNEL, TdT-mediated dUTP nick end labeling.


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