Inhibition of in vitro cytokine production by human peripheral blood mononuclear cells treated with xenobiotics: implications for the prediction of general toxicity and immunotoxicity.

The use of human peripheral blood mononuclear cells (PBMC) as an in vitro system to predict in vivo toxicity was investigated. For 58 chemicals, the effect on cytokine secretion (IL-5, IFNgamma and TNFalpha) by phytohaemagglutinin-activated PBMC was measured, IC50 values were calculated and correlations of these endpoints with human LC50 values were determined. The best result was obtained with IFNgamma as an endpoint for which the calculated R(2) value was 0.

Modulation of prolactin expression in human T lymphocytes by cytokines.

Besides its pivotal role in reproduction, the polypeptide hormone prolactin (PRL) has immunomodulatory properties. Whereas the bulk of circulating PRL is produced by the pituitary, PRL is also produced by the decidua, the myometrium, the mammary gland and leukocytes. Extrapituitary PRL expression is regulated differently from that in the pituitary, due to the use of an alternative promoter.

Multiple, PKA-dependent and PKA-independent, signals are involved in cAMP-induced PRL expression in the eosinophilic cell line Eol-1.

Besides its pivotal role in reproduction, the polypeptide hormone prolactin (PRL) has been attributed an immunomodulatory function. Extrapituitary PRL expression is regulated differently from that in the pituitary, due to the use of an alternative promoter. In leukocytes, cAMP is an important regulator of PRL expression.

Suppressor of cytokine signaling 7 inhibits prolactin, growth hormone, and leptin signaling by interacting with STAT5 or STAT3 and attenuating their nuclear translocation.

We report here the role of one of the less studied members of the family of suppressors of cytokine signaling (SOCS), namely SOCS-7, in cytokine signaling. We demonstrate that SOCS-7 inhibits prolactin (PRL), growth hormone (GH), or leptin (LEP) signaling mediated through STAT3 and STAT5 in a dose-dependent manner. SOCS-7 also attenuated STAT3 and STAT5 signaling induced by overexpression of JH1, the catalytic subdomain of JAK2.

Mechanism of prostaglandin (PG)E2-induced prolactin expression in human T cells: cooperation of two PGE2 receptor subtypes, E-prostanoid (EP) 3 and EP4, via calcium- and cyclic adenosine 5'-monophosphate-mediated signaling pathways.

We previously reported that prolactin gene expression in the T-leukemic cell line Jurkat is stimulated by PGE(2) and that cAMP acts synergistically with Ca(2+) or protein kinase C on the activation of the upstream prolactin promoter. Using the transcription inhibitor actinomycin D, we now show that PGE(2)-induced prolactin expression requires de novo prolactin mRNA synthesis and that PGE(2) does not influence prolactin mRNA stability. Furthermore, PGE(2)-induced prolactin expression was inhibited by protein kinase inhibitor fragment 14-22 and BAPTA-AM, which respectively, inhibit protein kinase A- and Ca(2+)-mediated signaling cascades.

Limited effect of selected organic pollutants on cytokine production by peripheral blood leukocytes.

To test the hypothesis that some persistent organic pollutants contribute to the increased prevalence of allergic disease, the effects of selected compounds on cytokine production by PBMC from control and allergic donors were evaluated. Cells were cultured for six days in the presence of a xenobiotic (PCB 153, hexachlorobenzene, pentachlorobenzene, pentachlorophenol, lindane, atrazine or DMSO vehicle) with phytohemagglutinin (PHA) or Dermatophagoides pteronyssinus extract, then for one day in the presence of PHA + phorbol 12-myristate 13-acetate. PCB 153 reduced the levels of IL-10, IFN-gamma and TNF-alpha.

The suppressor of cytokine signaling (SOCS)-7 interacts with the actin cytoskeleton through vinexin.

To understand the function of the suppressor of cytokine signaling (SOCS)-7, we have looked for proteins interacting with SOCS-7 in a stringent yeast two-hybrid screen of a human leukocyte cDNA-library. We identified the cytoskeletal molecule vinexin as a partner interacting with SOCS-7. Tests with deletion mutants of SOCS-7 demonstrated that a central region of the molecule containing several proline-rich regions, N-terminal to the SH2 domain, was responsible for the binding to vinexin.

IGF-I stimulates IL-8 production in the promyelocytic cell line HL-60 through activation of extracellular signal-regulated protein kinase.

Interleukin (IL)-8 serves as a major chemoattractant for neutrophils and has also been proposed to affect cancer progression. In the present study, we show that IGF-I stimulates IL-8 mRNA expression and IL-8 secretion in the leukemic cell line HL-60. Stimulation of IL-8 expression was completely attenuated by two inhibitors of mitogen-activated protein kinase (MAPK) kinase (MEK), which phosphorylates the MAPKs extracellular-regulated kinase (ERK)1 and ERK2, and by the c-Jun NH2-terminal kinase (JNK) inhibitor SP600125.

Clinical and biological characterization of macroprolactinemia with and without prolactin-IgG complexes.

Objective: Macroprolactinemia, which can be detected by a polyethylene glycol (PEG) precipitation test, is a clinically and biologically heterogeneous condition. In this study, we analyzed whether the clinical presentation, the hormonal findings and the in vitro lactogenic activity differed between macroprolactinemic patients with and without circulating prolactin (PRL)-IgG complexes.

Design: Clinical data were reviewed and additional hormonal studies were performed in 50 hyperprolactinemic patients with macroprolactinemia.

Effects of prolactin on cloned human T-lymphocytes.

To evaluate the possible role of prolactin (PRL) in T-lymphocytes, we monitored gene induction in one cytotoxic T-lymphocyte (CTL) clone derived from a patient with hemochromatosis and in several T-helper clones generated from a normal donor and a patient with multiple sclerosis. The CTL clone expressed conventional PRL receptor (PRLR), and PRL induced the expression of suppressor of cytokine signaling-3 (SOCS-3) and increased the expression of SOCS-2 and cytokine-inducible src homology-2 containing protein (CIS, another member of the SOCS family). As is the case in granulocytes, expression of a conventional receptor for PRL could not be shown by polymerase chain reaction analysis on three helper clones.

Inhibition of cytokine production by the herbicide atrazine. Search for nuclear receptor targets.

The hematological toxicity of the commonly used triazine herbicides is a cause for concern. In a search for molecular targets of these compounds, as their effects paralleled those seen with dexamethasone (DEX), we first looked for interaction with the glucocorticoid receptor. In contrast to the effects on proliferation and cytokine production of DEX, those induced by atrazine were not prevented by the glucocorticoid antagonist RU486.

Igf-I inhibits spontaneous apoptosis in human granulocytes.

Granulocytes are key cells in inflammatory processes that are recruited to sites of inflammation by chemoattractants such as IL-8 produced by neutrophils and monocytes. Programmed cell death (apoptosis) of granulocytes and subsequent recognition and phagocytosis by macrophages is a crucial mechanism for resolution of inflammation. Because IGF-I is a potent antiapoptotic factor, we addressed the effects of IGF-I on in vitro apoptosis of human peripheral blood granulocytes.