Because products of arachidonic acid metabolism, particularly the PG, have been implicated as modulators of growth and differentiation of adult thymocytes, we investigated relations between metabolism of arachidonic acid and growth, as well as differentiation, of thymocytes during fetal thymic organ culture. Fetal thymic cells synthesized immunoreactive PGE2 during organ culture and were found to be capable of metabolizing exogenous arachidonic acid to products that cochromatographed with authentic 6-keto-PGF1 alpha, PGE2, PGF2 alpha. Synthesis of these products and growth and expression of Thy-1 and Lyt-1 Ag were inhibited by culture of fetal thymic lobes with indomethacin, a cyclooxygenase inhibitor, as well as meclofenamate and eicosatetraynoic acid, inhibitors of cyclooxygenase and lipoxygenase pathways of arachidonic acid metabolism. Only indomethacin inhibited expression of Lyt-2. Culture with eicosatetraynoic acid also inhibited the capacity of thymic lobes to synthesize 15-hydroxyeicosatetraenoic acid-like products. The inhibitory effects of indomethacin on growth and expression of Thy-1 were partially reversed by simultaneous addition of arachidonic acid. Thus, fetal thymic cells appear to require an intact cyclooxygenase, and possibly lipoxygenase, pathway of arachidonic acid metabolism for growth and differentiation. These data also provide evidence that Lyt-1 and Lyt-2 may be regulated by different requirements with respect to arachidonic acid metabolism.

Mice homozygous for the autosomal recessive mutation wasted (wst/wst) undergo a progressive wasting beginning at the third week of postnatal life, when body weight declines in the mutants. The wst/wst mice do not survive past 30 days of age. The present report describes histologic and functional abnormalities in a longitudinal analysis (17 to 29 days postpartum) of wst/wst mice. In addition to a marked age-dependent decline in wst/wst body weight as well as spleen and thymus wet weight to body weight ratios, we have observed a significant decline in spleen and thymus cell number in these organs, compared with phenotypically normal (+/+ or +/wst) littermates. Histologic analysis of the wst/wst thymus revealed marked cortical pyknosis at 23 days of age and significant cortical depletion by 26 days postpartum. The wst/wst spleen at 23 days of age and later was characterized by a marked reduction in the content of red pulp. Lymphoproliferative responsiveness to Con A was markedly altered in the wst/wst thymus and spleen, in an age-dependent fashion, compared with normal littermates. The wst/wst spleen LPS responsiveness was also markedly altered in an age-dependent fashion. Hypotheses are presented concerning the possible site(s) of gene action in the wst/wst mutant which may mediate the observed morphologic and functional abnormalities.

No abstract