Induction and regulation of matrix metalloproteinase-12 by cytokines and CD40 signaling in monocyte/macrophages.

Matrix metalloproteinase-12 (MMP-12) has been shown to play critical roles in atherogenesis. To determine the cellular mechanisms for control of MMP-12 expression, we studied the effects of several cytokines (GM-CSF, IL-1beta, MCP-1) and CD40 ligand on MMP-12 expression in human monocyte/macrophages. Undifferentiated U937 monocytic cells and human peripheral blood monocytes did not express MMP-12. However, in the presence of GM-CSF, these monocytes showed MMP-12 expression at both the transcriptional and protein levels. The combination of treatment with GM-CSF and IL-1beta or MCP-1 resulted in a further increase of MMP-12 expression compared to treatment with GM-CSF alone. By contrast, both U937-derived macrophages and human peripheral blood monocyte-derived macrophages showed spontaneous MMP-12 expression, which was significantly increased by the addition of either GM-CSF or anti-CD40Ab. These results indicate that expression of MMP-12 is dependent upon the state of cellular differentiation and enhanced by cytokines and CD40 signaling.

Effects of suprachiasmatic transplants on circadian rhythms of neuroendocrine function in golden hamsters.

Grafts of fetal tissue including the suprachiasmatic nucleus (SCN) of the hypothalamus restore locomotor rhythmicity to behaviorally arrhythmic, SCN-lesioned Syrian hamsters. We sought to determine whether such transplants also reinstate endocrine rhythms in SCN-lesioned hamsters. In Exp 1, SCN lesions interrupted estrous cycles in a 14 h light, 10 h dark photoperiod and locomotor rhythms in constant dim red light (DD). SCN grafts that reinstated behavioral circadian rhythms consistently failed to reestablish estrous cycles. After ovariectomy, estradiol implants triggered LH surges at approximately circadian time 8 in 10 of 12 brain-intact control females and 0 of 9 SCN-lesioned, grafted females. Daily rhythms of the principal urinary melatonin metabolite, 6alpha-sulfatoxymelatonin, were not reestablished by behaviorally functional grafts. In Exp 2, SCN lesions eliminated locomotor rhythmicity in adult male hamsters maintained in DD. Seven to 12 weeks after restoration of locomotor activity rhythms by fetal grafts, hosts and sham-lesioned controls were decapitated at circadian times 4, 8, 12, 16, 20, or 24. Clear circadian rhythms of both serum corticosterone and cortisol were seen in sham-lesioned males, with peaks in late subjective day. No circadian rhythms in either adrenal hormone were evident in serum from lesioned-grafted males. Testicular regression, observed in intact and sham-lesioned males maintained in DD, was absent not only in arrhythmic SCN-lesioned hamsters given grafts of cerebral cortex, but also in animals in which hypothalamic grafts had reinstated locomotor rhythmicity. The pineal melatonin concentration rose sharply during the late subjective night in control hamsters, but not in SCN-lesioned animals bearing behaviorally effective transplants. Even though circadian rhythms of locomotor activity are restored by SCN transplants, circadian endocrine rhythms are not reestablished. Endocrine rhythms may require qualitatively different or more extensive SCN outputs than those established by fetal grafts.