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Introduction: Communication between neuroendocrinne and immune system is arranged by hormones and cytokines in endocrinne, paracrinne and autocrinne manner. One of the factors involved is also prolactin, a pituitary hormone and an immune cytokine. Sepsis is a system reaction to inflammation mediated by Th1 immune response, which is supported by prolactin as well. Primary protection against sepsis is mediated by innate immunity. Toll- like receptors distinguish molecules, which are connected with pathogens. Afterwards this identification of a specific pathogen toll-like receptors trigger immune reaction with the main goal of destroying this pathogen and also with the goal of renewing the balance of the organism. It is supposed that in the organism that is hardly attacked by a pathogen, the PRL, TLR2 and TLR4 gene expression is on the increase. We studied the levels of PRL, TLR2 and TLR4 mRNA production in circulating monocytes derived from septic patients. Simultaneously, the effect of PRL -1149 G/T SNP on physiological levels of PRL mRNA and its expression in the course of sepsis was evaluated. Materials and methods: As a source of monocytes, blood specimens from 43 septic patients and 40 healthy controls were used. The blood of septic patients was taken three times with some time difference and...

Xiao Ping. / "September 2004." / Thesis (Ph.D.)--Chinese University of Hong Kong, 2004. / Includes bibliographical references (p. 153-176) / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Mode of access: World Wide Web. / Abstracts in English and Chinese.

Prolactin (PRL) and its receptor (PRLr) have been implicated in the development and progression of human breast cancer. PRL activates its receptor and induces activation of proximal Janus kinase 2 (Jak2) for signal transduction. Here, we sought to determine the role of PRLr-associated peptidyl-prolyl isomerase, cyclophilin A (CypA), in modulating structure/function relationships of the PRLr. It was demonstrated that CypA mediated PRL-induced conformational change of the CFP- and -YFP tagged forms of the PRLr cytoplasmic-tail, whereas CypA inhibition by NIM811 (N-methyl-4-isoleucine cyclosporin) or knockdown blocked the conformational change of the PRLr assessed by Fluorescence Resonance Energy Transfer (FRET) signal or efficiency. To further investigate the consequences of CypA inhibition or knockdown on the PRLr/Jak2 complex mediated signaling/functions, analyses of phospho-tyrosine residues that are believed to be important for interactions/signaling were investigated. It was found that NIM811 inhibition or CypA shRNA knockdown significantly reduced prolactin-stimulated phosphorylation of PRLr/Jak2 intermediates and their association with the PRLr in breast cancer cells. A microarray analysis revealed that NIM811 inhibited approximately 66% of the top 50 PRL-induced genes. NIM811 inhibited breast cancer cell proliferation, survival, migration and anchorage-independent growth. Subsequent NIM811 treatment of a triple negative breast cancer xenograft inhibited primary tumor growth, outgrowth of macro-metastasis and induced central tumor necrosis. Furthermore, loss of CypA in the MMTV-PyMT mouse model demonstrated inhibition of tumorigenesis with significant reduction in lung and lymph node metastasis. Overall, CypA modulates PRL-induced conformational change of the C-terminus of the PRLr through its isomerase activity, altering PRLr/Jak2 complex signaling/functions in breast/mammary tumorigenesis and metastasis.

Genetic predisposition and exposure to alcohol and stress increase the risk for alcoholism, possibly by forming a threefold interaction. This is suggested by various aspects of alcohol-induced stress response dampening in offspring of alcoholics. We tested whether such an interaction is also revealed by prolactin secretion, which is predominantly controlled by hypothalamic dopamine. Plasma prolactin was measured during four experimental days in 26 young males with a paternal history of alcoholism (PHA) and in 22 family history negative (FHN) controls. A public speaking stress paradigm was applied on the first 2 days, and a non-stress acoustic startle experiment on the others. Before the tests, subjects drank alcohol (0.6 g/kg) or placebo in a randomized, double-blind crossover design. During placebo experiments, prolactin levels significantly increased after stress, but not after startle, and did not differ between risk groups. Alcohol administration significantly increased prolactin before stress and during startle in both groups, did not alter stress-induced prolactin stimulation in FHN, but significantly attenuated the prolactin stress response in PHA subjects. The alcohol effects on prolactin, cortisol, and adrenocorticotropin stress response were positively interrelated with each other. These data confirm that alcohol specifically dampens the stress response in PHA but not FHN subjects. Since prolactin responses to stress alone and alcohol alone were normal in PHA, we conclude that this genetic effect is not related to altered physiology of the hypothalamic dopaminergic system, but to risk-group specific alcohol effects on hierarchically higher brain areas controlling the stress response in general.