No abstract

Administration of ␤-sitosterol (42 mg/kg per day) for 3 weeks to 8-month-old male LXR␤ ؊/؊ mice resulted in the death of motor neurons in the lumbar region of the spinal cord and loss of tyrosine hydroxylase-positive dopaminergic neurons in the substantia nigra. In mice at 5 months of age, ␤-sitosterol had no observed toxicity but at 16 months of age, it caused severe paralysis and symptoms typical of dopaminergic dysfunction in LXR␤ ؊/؊ mice. WT mice were not affected by these doses of ␤-sitosterol. In 5-month-old mice, levels of the intestinal transporters, ABCG5/8 and Niemann-Pick C1 Like 1, were not affected by loss of liver X receptor (LXR) ␤ and/or treatment with ␤-sitosterol nor were there changes in plasma levels of cholesterol or ␤-sitosterol. In 8-monthold LXR␤ ؊/؊ mice there was activation of microglia in the substantia nigra pars reticulata and aggregates of ubiquitin and TDP-43 in the cytoplasm of large motor neurons in the lumbar spinal cord. Brain cholesterol concentrations were higher in LXR␤ ؊/؊ than in their WT counterparts, and treatment with ␤-sitosterol reduced brain cholesterol in both WT and LXR␤ ؊/؊ mice. In LXR␤ ؊/؊ mice but not in WT mice levels of 24-hydrocholesterol were increased upon ␤-sitosterol treatment. These data indicate that multiple mechanisms are involved in the sensitivity of LXR␤ ؊/؊ mice to ␤-sitosterol. These include activation of microglia, accumulation of protein aggregates in the cytoplasm of large motor neurons, and depletion of brain cholesterol.central nervous system ͉ cholesterol ͉ microglia ͉ neurodegenerative disease ͉ nuclear receptor

Estrogen receptor b (ERb) is expressed in immune cells and studies have suggested an antiproliferative function of ERb. We detected ERb expression in murine T-and human B-cell lymphoma cell lines and analyzed the effects of estradiol and selective ERb agonists on lymphoma growth in culture and in vivo. Treating the cells with estradiol had minor effects on cell growth, whereas the selective ERb agonists diarylpropionitrile (DPN) and KB9520 showed a strong antiproliferative effect. When grafting mice with murine T-cell lymphoma cells, male mice developed larger tumors compared with female mice, a difference that was abolished following ovariectomy, showing estrogen-dependent growth in vivo. To investigate whether lymphoma growth may be inhibited in vivo by ERb agonist treatment, mice grafted with murine lymphoma cells were treated with DPN or KB9520. Both ERb-selective agonists strongly inhibited lymphoma growth. The reduced tumor size seen following either DPN or KB9520 treatment was due to reduced proliferation and increased apoptosis. Our results show an ERb ligand-dependent antiproliferative effect of lymphoma cells expressing endogenous ERb and that lymphoma cell growth in vivo can efficiently be inhibited by ERb agonists. This suggests that ERb agonists may be useful in the treatment of lymphomas.

Key Points Estrogen receptor β (ERβ) activation inhibits lymphoma growth, vascularization, and dissemination in vivo. ERβ activation may mechanistically explain differences in gender incidence and prognosis and contribute to new therapies of lymphomas.

The appearance of newly translated group 1 CD1 proteins (CD1a, CD1b, CD1c) on maturing myeloid DC to effective lipid antigen presenting cells. Here we show that Borrelia burgdorferi, the causative agent of Lyme disease, triggers appearance of group 1 CD1 proteins at high density on the surface of human myeloid DC during infection. Within human skin, CD1b and CD1c expression was low or absent prior to infection, but increased significantly after experimental infections and in erythema migrans lesions from Lyme Disease patients. The induction of CD1 was initiated by borrelial lipids acting through TLR-2 within minutes, but required 3 days for maximum effect. The delay in CD1 protein appearance involved a multi-step process whereby TLR-2 stimulated cells release soluble factors, which are sufficient to transfer the CD1-inducing effect in trans to other cells. Analysis of these soluble factors identified IL-1β as a previously unknown pathway leading to group 1 CD1 protein function. These studies establish that upregulation of group 1 CD1 proteins is an early event in B. burgdorferi infection and suggest a stepwise mechanism whereby bacterial cell walls, TLR activation and cytokine release cause DC precursors to express group 1 CD1 proteins.