Background. Lethal midline granuloma is now considered to be a malignant lymphoma derived from peripheral T cells or from natural killer cells. The therapeutic outcome of nasal T‐cell lymphoma (NL) treated by conventional chemotherapy for non‐Hodgkin's lymphoma is poor, although some patients have a good response to radiotherapy. To clarify the mechanisms of drug resistance, the expression of P‐glycoprotein (P‐gp)/MDR1, which is the product of the multidrug resistance (MDR) 1 gene, and MDR3 mRNA in NL cells, were examined. Methods. Ten Japanese patients with NL were studied. Nine of these patients were examined before therapy. P‐glycoprotein expression and phenotypes of lymphoma cells were examined by immunohistochemical staining using UIC2 as an anti–P‐gp monoclonal antibody. In one case, the Rhodamine‐123 efflux test was performed. MDR1 and MDR3 mRNA were detected by reverse transcription polymerase chain reaction. Results. Nine of the 10 patients were P‐gp positive. In one of nine, functional P‐gp expression was observed. MDR1 mRNA was detected in all seven examined patients with P‐gp positive NLs, whereas MDR3 mRNA was negative. Retrospectively, patients who received chemotherapy alone had poorer outcome than those treated by combination chemotherapy after irradiation. Conclusion. The poor prognosis for patients with NL treated with chemotherapy may be explained by P‐gp expression of the NL cells. Cancer 1995; 76:2351–6.

Renal enlargement in polycystic kidney disease (PKD) is caused by the proliferation of mural epithelial cells and transepithelial fluid secretion into the cavities of innumerable cysts. Arginine vasopressin (AVP) stimulates the proliferation of human PKD cells in vitro via cAMP-dependent activation of the B-Raf/MEK (MAPK/ERK kinase/extracellular signalregulated kinase (ERK) pathway. ERK activity is elevated in cells that line the cysts in animals with PKD, and AVP receptor antagonists reduce ERK activity and halt disease progression. For suppression of the effect of AVP physiologically, water intake was increased in PCK rats, a model of PKD, and the effect on renal morphology, cellular mechanism, and function was determined. The addition of 5% glucose in the drinking water increased fluid intake approximately 3.5-fold compared with rats that received tap water. In PCK rats, increased water intake for 10 wk reduced urinary AVP excretion (68.3%), and urine osmolality fell below 290 mOsmol/kg. High water intake was associated with reduced renal expression of AVP V2 receptors (41.0%), B-Raf (15.4%), phosphorylated ERK (38.1%), and proliferating cell nuclear antigen-positive renal cells (61.7%). High water intake reduced the kidney/body weight ratio 28.0% and improved renal function. Taken together, these data demonstrate that water intake that is sufficient to cause persistent water diuresis suppresses B-Raf/MEK/ERK activity and decreases cyst and renal volumes in PCK rats. It is suggested that limiting serum AVP levels by increased water intake may be beneficial to some patients with PKD.

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Summary. Peripheral blood monocytes are common precursor cells of dendritic cells (DCs) and macrophages. We have searched for factors with the potential to regulate the differentiation of monocytes to DCs and macrophages. When CD141 monocytes are cultured with granulocyte± macrophage colony-stimulating factor (GM-CSF) and interleukin (IL) 4, the CD14 1 CD1a 2 population, which consists of macrophages, was found in the serum-containing cultures but not in the serum-free cultures. Addition of IL-6 receptor-neutralizing monoclonal antibody (mAb) or gp130-neutralizing mAb to the serum-containing cultures resulted in a decreased population of CD141 CD1a 2 cells. An increase in the CD141 CD1a 2 population with reduction in CD14 2 CD1a 1 DCs was observed with the addition of IL-6 to cultures, whereas IL-11, leukaemia inhibitory factor, oncostatin M or macrophage colony-stimulating factor did not affect the differentiation of monocytes in the presence of GM-CSF plus IL-4. This effect of IL-6 was blocked by tumour necrosis factor a (TNF-a), lipopolysaccharide (LPS), IL-1b, CD40 ligand (CD40L) and transforming growth factor b1 (TGF-b1). Among these factors, TNF-a was most potent in interfering with the action of IL-6. These results suggest that IL-6 inhibits the differentiation of monocytes to DCs by promoting their differentiation toward macrophages, which is modulated by factors such as TNF-a, LPS, IL-1b, CD40L and TGF-b1.

Human Langerhans cells (LCs) are of hematopoietic origin, but cytokine regulation of their development is not fully understood. Notch ligand Delta-1 is expressed in a proportion of the skin. Granulocyte-macrophage colony-stimulating factor (GM-CSF) and transforming growth factor-beta1 (TGF-beta1) are also secreted in the skin. We report here that Delta-1, in concert with GM-CSF and TGF-beta1, induces the differentiation of human CD14(+) blood monocytes into cells that express LC markers: CD1a, Langerin, cutaneous lymphocyte-associated antigen, CC chemokine receptor 6, E-cadherin, and Birbeck granules. The resulting cells display phagocytic activity and chemotaxis to macrophage inflammatory protein-1alpha (MIP-1alpha). In response to CD40 ligand and tumor necrosis factor alpha, the cells acquire a mature phenotype of dendritic cells that is characterized by up-regulation of human leukocyte antigen (HLA)-ABC, HLA-DR, CD80, CD86, CD40, and CD54 and appearance of CD83. These cells in turn show chemotaxis toward MIP-1beta and elicit activation of CD8(+) T cells and T helper cell type 1 polarization of CD4(+) T cells. Thus, blood monocytes can give rise to LCs upon exposure to the skin cytokine environment consisting of Delta-1, GM-CSF, and TGF-beta1, which may be, in part, relevant to the development of human epidermal LCs. Our results extend the functional scope of Notch ligand delta-1 in human hematopoiesis.