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Serum prolactin is associated with apoptosis in men with human immunodeficiency virus infection
Seville, 26. July 2010
We examined the in vivo and in vitro production of prolactin (PRL) in 20 untreated HIV-infected men compared to 14 uninfected men and its association with the cell cycle and apoptosis. Compared to uninfected men, the HIV-infected men had: (i) higher fasting serum bioactive (BIO) PRL; (ii) lower serum immunoreactive (RIA) and BIO-PRL responses to intravenous metoclopramide; (iii) greater BIO-RIA PRL ratio both fasting and during intravenous metoclopramide; (iv) lower percentage of non-stimulated PBMC in the G0/G1 phase, but a higher percentage in the S phase, of the cell cycle with normal response to Concanavalin-A; and (v) higher in vitro production of BIO-PRL by non-stimulated PBMC, which was blocked after Concanavalin-A. Fasting serum BIO-PRL positively correlated with the percent of non-stimulated PBMC in S + G2/M phases. The percentage of apoptotic PBMC negatively correlated with CD4+ T lymphocytes and with the area under the serum RIA?PRL curve, but positively correlated with the area under the curve for the BIO/RIA ratio. These results suggest that in these HIV-infected men: (i) a diminished dopaminergic tone may exist, as an adaptive mechanism attempting to survive; and (ii) BIO-PRL may participate as a cofactor in the stimulation of T-cell proliferation.
The synthesis of prolactin (PRL) is not limited to the pituitary as many other extra-pituitary tissues, including T lymphocytes can produce PRL.This hormone has a prominent immunomodulatory role both in humoral and cell-mediated immune responses by acting at the endocrine, paracrine and autocrine levels.Under physiological conditions the production of PRL by the pituitary is mainly under the control of a tonic inhibitory mechanism mediated by dopamine (DA) acting through dopamine D2 receptors in the lactotrophs;however, the mechanisms controlling the production of PRL in extra-pituitary sites remains largely unknown. This seems to be a relevant issue, as hypophysectomized rats show a postoperative rise in serum PRL concentrations and depend on this residual PRL for survival.In other words, it seems that when the main source of PRL production is abolished, extra-pituitary PRL could be exported into the general circulation and accumulated through endocytosis by other cells to fulfil important biological actions.
Animal and human studies have demonstrated that PRL functions as a necessary comitogen for different cell types, including human T and B cells, and by acting through the PRL receptors present in these cells PRL stimulates both cell proliferation and survival. Furthermore, PRL facilitates the progression of the cell cycle, both in PRL-dependent and PRL-independent cell lines and is considered to be an anti-apoptotic hormone as opposed to glucocorticoids.
Critically ill patients receiving a DA infusion had a marked reduction in serum PRL levels simultaneously with an immediate, although transitory, decrease in the in vitro T-cell response to Concanavalin-A. This, together with the recent demonstration that the DA concentration within human lymphocytes (which depends both on lymphocyte synthesis and uptake of extracellular DA) functions as an autocrine loop whereby lymphocytes downregulate their own proliferative activity, highlights the importance of exploring, directly or indirectly, the possible interplay within human lymphocytes of PRL and DA, both in healthy and ill humans.
Despite the overwhelming information regarding the possible role of PRL, especially biologically active PRL, in HIV infection, this area has remained largely unexplored. Nevertheless, some studies have suggested indirectly that the existence of a low DA tone in men with HIV-infection could represent an adaptive mechanism attempting to stimulate human lymphocyte proliferation at a maximum possible rate in an attempt to survive. The aim of the present study was to explore the in vivo and in vitro production of bioactive PRL in a group of untreated HIV-infected men and its association with the cell cycle and apoptosis of PBMC in these patients.