A. V. Zhdanov

Disorders in Cytokine Gene Expression in Endometrial Hyperplasia and Effect of Hormone Therapy

We studied local expression of insulin-like growth factor 1, insulin-like growth factor receptor, epithelial growth factor, transforming growth factor β2, PCNA, TNF-α, type I TNF receptor, Fas, FasL, IFN-γ, IL-1β, IL-4, IL-6, IL-8, IL-10, and IL-12 genes in intact and hyperplastic endometrium. Endometrial hyperplasia was associated with reduced production of TNF-α (p<0.05), PCNA (p<0.05), and epithelial growth factor mRNA and enhanced production of Fas mRNA (p<0.01). The expression of TNF-R1, IL-1β, and IL-12 genes decreased only in glandular cystic hyperplasia (p<0.05 for all genes), expression of insulin-like growth factor 1 gene decreased only in adenomatous hyperplasia (p<0.05). Dufaston therapy of glandular cystic hyperplasia and zoladex therapy of adenomatous hyperplasia normalized expression of Fas receptor, PCNA, and insulin-like growth factor 1 genes, while the expression of IFN-γ and IL-6 genes, which was normal in hyperplasia, decreased (p<0.05). Zoladex therapy decreased the production of transforming growth factor β2 (p<0.05) and IL-1β (p<0.01) mRNA, dufaston therapy decreased production of TNF-α (p<0.05) and IL-4 mRNA (p<0.05). Hence, both apoptosis and proliferative activity were suppressed in endometrial hyperplasia, and hormone therapy created prerequisites for transition of the endometrium into the normal proliferation stage.

Apoptosis in fimbriae of fallopian tubes and endometrium in pyoinflammatory adnexal diseases.

In patients with pyoinflammatory adnexal diseases moderate or intense DNA degradation was observed in the majority of epithelial, stromal, and inflammatory infiltration cell in inflammatory foci in the fimbrial compartment of fallopian tubes without signs of tissue destruction. Expression of TNFR1 gene increased 2.7-fold and expression of Fas gene decreased 3.1-fold compared to intact endosalpinx, which indicates induction of apoptosis triggered by tumor necrosis factor-α and inhibition of the Fas-dependent pathway. No signs of apoptosis were detected in the endometrium. Generalized apoptosis in the fimbrial compartment of the tubes can be a mechanism limiting the inflammatory process.

Correlations in the Cytokine System in Endometrial Hyperplasia

Correlations between local expression of insulin-like growth factor 1, insulin-like growth factor receptor, epithelial growth factor, transforming growth β2 factor, PCNA, TNF-α, TNF receptor 1, Fas, FasL, IFN-γ, IL-1β, IL-4, IL-6, IL-8, IL-10, and IL-12 genes in intact and hyperplastic endometrium and in the endometrum after hormone therapy were analyzed. Numerous correlations at the proliferation and secretion stages of the menstrual cycle indicate balanced cytokine system. The number of correlations decreases in glandular cystic and more so in atypical hyperplasia, indicating imbalance in the cytokine system. Dufastone and zoladex therapy did not lead to recovery of this balance, but higher correlations between the expression of some factors of cell proliferation attest to the beginning of normalization of pathologically changed endometrium.

Apoptosis in woman uterine cervix in pathologies associated with human papillomavirus.

The level of apoptosis in uterine cervical tissue was evaluated in healthy women and in patients with various pathologies. No signs of apoptosis were found in unchanged stratified epithelium, condyloma latum, and condyloma acuminatum. The level of apoptosis decreased with progression of neoplastic epithelial transformations, usually no apoptosis was observed in samples of stage III cervical intraepithelial neoplasms. The development of preinvasive carcinoma was accompanied by activation of apoptotic processes most pronounced in the upper third of the epithelium. In some stage I and stage I-II cervical intraepithelial neoplasms, apoptosis and elimination of the basal layer cells caused rejection of the epithelium which can explain regression of this pathology at the initial stages. The prevalence of human papillomavirus infection directly correlated with neoplastic changes in the cervical epithelium.

Location and intensity of IL-8 and TGF-beta2 mRNA production in the fimbrial compartment of fallopian tubes and IL-10 in the endometrium in patients with pyoinflammatory adnexal diseases.

The location and level of IL-8 and TGF-β2 expression in the fimbrial compartment of fallopian tubes and IL-10 expression in the endometrium of women with pyoinflammatory adnexal diseases were studied by in situ hybridization. These diseases are associated with considerable changes in the levels of local production of these cytokines. Inflammatory infiltration and epithelial cells were most active producers of IL-9 and TGF-β2 in the fimbrial compartment of fallopian tubes, while in the endometrium IL-10 gene was expressed at a high level primarily in the glandular epithelial cells.

Expression of cytokine genes in adhesions on uterine tubes.

We studied expression of genes of interleukins, interferon-γ, tumor necrosis factor-α, and transforming growth factor-β2 in adhesions on uterine tubes. In tubal adhesions the intensity of production of mRNA for proinflammatory cytokines, antiinflammatory cytokine interleukin-10, and regulator of cell proliferation surpassed that in normal tissues by 2.5-7.4, 2.2, and 50.2 times, respectively. Correlations were found between production of mRNA for tumor necrosis factor-α and transforming growth factor-β2, interleukin-12, and interferon-γ and interleukin-12 and transforming growth factor-β2. Our results suggest that expression of these genes during adhesion formation is regulated by the feedback mechanism.

Expression of cytokine genes in blood mononuclear cells in women with pyoinflammatory diseases of adnexa uteri.

Production of interleukin, interferon-γ, and transforming growth β2-factor mRNA in peripheral blood mononuclear cells was studied in women with pyoinflammatory diseases of adnexa uteri. Predominant expression of Th1 proinflammatory cytokine genes in patients was demonstrated. Production of interleukins 4 and 8 mRNA decreased 200- and 60-fold, respectively, in comparison with that in healthy women. One month and a half after extirpation of fallopian tubes the cytokine production in blood mononuclear cells shifted towards antiinflammatory cytokines, expression of interleukin-8 gene returned to normal, and expression of interleukin-4 gene increased.

Local expression of cytokine genes in uterine adnexa and endometrium of women with pyoinflammatory adnexal diseases.

Changes in the local expression of IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12, IL-15, IL-18, TNF-α, IFN-γ- and TGF-β2 genes in the uterine adnexa and endometrium were studied in women with pyoinflammatory adnexal diseases. Examination of tissue specimens from the uterine adnexa involved in inflammation revealed a direct correlation in the levels of mRNA production between IL-6 and IL-10 (r=0.93, p<0.1), IL-6 and IL-4 (r=0.96, p<0.01), IL-10 and IL-4 (r=0.91, p<0.01), IL-12 and IFN-γ (r=0.98, p<0.01). Expression of IL-4 gene increased 5.1-fold (p=0.001), IL-6 2-fold (p=0.007), IL-8 90.2-fold (p=0.009), IL-10 2.9-fold (p=0.008), IL-12 2.3-fold (p=0.3), and TGF-β2 gene 10.3-fold (p=0.1). In the endometrium of women with pyoinflammatory adnexal diseases only IL-10 gene expression increased (15.6-fold, p=0.007).

Interferon system in women with genital papillomavirus infection receiving immunomodulatory therapy.

The interferon system was studied in women with genital papillomavirus infection. In most patients the interferon system was activated, while the ability of lymphocytes to respond to inductors decreased. Laserotherapy and immunomodulatory therapy with larifan, ridostin, and viferon for 1 month normalized blood interferon concentration (39.4% patients) and interferon-γ production by lymphocytes in response to inductors (87.9% patients). After laser monotherapy these parameters returned to normal only in 13.2 and 7.6% patients, respectively. Correlation and regression analyses showed that changes in the interferon system were synchronized after immunomodulatory therapy. These data indicate that immunomodulatory therapy produces a complex effect on the interferon system. Measurements of blood interferon level can be used to predict the effect of further treatment with interferon-γ inductors.

Suppressed production of transforming growth factor-beta(2)mRNA in endometrium of women with polycystic ovary syndrome.

Production of transforming growth factor-β2 mRNA in the endometrium of women with polycystic ovary syndrome decreased compared to normal and this decrease directly depends on the duration of anovulatory period (from 3 weeks to 4 months). Low production of transforming growth factor-β2 mRNA probably contributes to the development of endometrial hyperplasia in women with polycystic ovary syndrome.