Estrogen decreases expression of chemokine receptors, and suppresses chemokine bioactivity in murine monocytes

Problem:  We propose that the ability of estrogen exposure to increase the probability of a woman developing breast cancer may be related to decreased chemokine activity and suppression of immune surveillance in mammary tissue. The present study was conducted to determine whether estrogen could decrease monocyte bioactivity through alteration of chemokine receptor expression.
Method of study:  We examined the effect of estrogen and tamoxifen on the expression of the chemokine receptors CCR2 and CXCR3 on murine monocytes treated in culture and in vivo . Effects of estrogen on chemokine activation of monocytes were also evaluated.
Results:  Estrogen and tamoxifen significantly decreased expression of CCR2 and, to a lesser extent, CXCR3 on murine monocytes. Estrogen decreased chemotaxis of monocytes towards MCP-1/JE. The chemokines MCP-1/JE and MIP-1 α were unable to evoke increases in intracellular calcium in murine monocytes treated with estrogen, alone or in combination with tamoxifen.
Conclusions:  Our results show that estrogen suppresses the ability of monocytes to respond to certain chemokines, suggesting that estrogen exposure might decrease immune surveillance in tissues where the action of specific chemokines is involved.     

Endogenous animal models of intracranial aneurysm development: a review

Neurosurgical Review - The pathogenesis and natural history of intracranial aneurysm (IA) remains poorly understood. To this end, animal models with induced cerebral vessel lesions mimicking human...     

Estrogen Disrupts Chemokine-Mediated Chemokine Release from Mammary Cells: Implications for the Interplay between Estrogen and IP-10 in the Regulation of Mammary Tumor Formation

Chemokines are pro-inflammatory cytokines that function to attract immune cells to the sites of tissue inflammation, injury or infection. We have formulated the hypothesis that release of one chemokine can serve, in a local paracrine or endocrine fashion, to induce the release of other chemokines from neighboring mammary cells. We set out to investigate whether specific chemokines could promote the release of other chemokine members from mammary cells, and whether estrogen could serve to disrupt the release of these chemokines from mammary cells. We found that treatment with the chemokine IP-10 resulted in significant increases in the amount of MIP-1alpha and MCP-1/JE released from murine mammary cells. Estrogen co-treatment significantly blocked the ability of IP-10 to trigger the release of MIP-1alpha and MCP-1/JE. Suppressive effects of estrogen were reversed upon co-treatment with 4-hydroxytamoxifen. Estrogen treatment significantly decreased expression of proteins corresponding to the chemokine receptors CXCR3 and CCR5 on mammary cells. Exposure of female mice to IP-10 in vivo significantly decreased the ability of estrogen to support the growth of CCL-51-based tumors in mammary tissue. Our results suggest that exposure of mammary tissue to estrogen may decrease the release of local chemokines from mammary cells, potentially increasing the risk of tumor growth through decreased immune surveillance. Ongoing studies are investigating the possible mechanisms through which IP-10 stimulates the release of chemokines from mammary cells, and how the action of IP-10 may serve to decrease mammary tumor formation.     

Outcome and risks of ultra-long-term treatment with an oral neuroleptic drug. Relationship between perazine serum levels and clinical variables in schizophrenic outpatients

In 33 schizophrenic patients treated continuously as outpatients with perazine over two decades, the rehospitalization rate decreased from 0.58 before treatment to 0.07 during treatment. The intensity of psychopathologic symptoms and the side effects were found to be remarkably low. The high intraindividual constancy of perazine plasma levels and the tight correlation between dose and plasma levels indicated satisfactory patient compliance. Plasma levels amounted to only 25% of those under acute treatment and correlated positively with the severity of the disease. Higher plasma levels coincided with more frequent side effects such as slightly pathologic liver function and moderate impairment of oral glucose tolerance. The results suggest that low-dose maintenance treatment of schizophrenic patients with oral neuroleptics is effective and relatively safe.     

Psychoendocrinological and therapeutic effects of TRH in depression.

The antidepressive efficacy of TRH was investigated in 15 endogenous depressive patients in a double-blind cross-over design. The Hamilton depression scale, the AMP (PAS) system, v. Zerssen scale and thermometer scales were used. No therapeutic effect could be demonstrated. The blunted TSH-response to TRH, which has been described by other investigators, was confirmed. There was suggestive evidence of a psychoendocrinological relationship in the sense that the more severe the "somatic depressive" syndrome as calculated from the AMP system, and the more marked the diurnal variation of the endogenous type is, the lower are the basal TSH-values and the smaller the response to TRH. Thus, TRH may become a useful tool to identify subgroups of depressive patient populations.     

Relationship between perazine serum concentration and clinical results in long-term treated schizophrenic outpatients (author's transl)]

The perazine serum concentration was determined with a new gaschromatographic method in 33 schizophrenic outpatients of our psychiatric catamnestic unit who had received perazine for a period of 18 years. A very high constancy of the perazine serum level could be demonstrated by repeated measurements. A close connection existed between perazine dosage and perazine serum level. Both findings suggest a very good complicance of these patients. Serum levels were correlated positively with the intensity of the psychopathologic symptoms as well as with the frequency of side-effects, particularly with slight changes of liver enzymes.     

Estrogen decreases chemokine levels in murine mammary tissue

Estrogen contributes to the development of breast cancer through mechanisms that are not completely understood. Estrogen influences the function of immune effector cells, primarily through alterations in cytokine expression. Chemokines are proinflammatory cytokines that attract various immune cells to the site of tissue injury or inflammation, and activate many cell types, including T lymphocytes and monocytes. As an initial step toward ultimately determining whether regulation of chemokine expression and/or biological activity by estrogen could potentially be a contributing factor to the development and progression of mammary tumors, we evaluated the effect of estrogen on the expression of specific chemokines in murine mammary tissue. We also evaluated whether exposure of female mice to various chemokines could alter the growth of mammary tumors in the presence of estrogen. We report here that estrogen significantly decreases levels of the chemokines MIP-1α and MCP-1/JE in murine mammary tissue. Co-treatment with 4-hydroxytamoxifen partially reverses the suppressive effect of estrogen on MIP-1α levels. Estrogen increases the growth of CCL-51 cell-based tumors in the mammary glands of female mice. Co-treatment with the chemokine MIP-1α or MCP-1/JE substantially decreases the ability of estrogen to stimulate the formation of CCL-51 cell-based tumors. Our results show that estrogen might influence the bioactivity of specific chemokines through alteration of chemokine expression in mammary tissue, and further suggest that decreases in murine chemokines evoked by estrogen exposure could contribute to the promotion of mammary tumor growth. An erratum to this article is available at .