ABSTRACT
AIMS: Immune factors influencing the progression of cervical intraepithelial neoplasia (CIN) to cancer remain poorly defined. This study investigates the expression of RANTES, MIP1alpha, COX1, COX2, STAT3, TGFbetaRI, IL10R, TNFalphaRII and TLR4 in the cervical immune response in HIV/HPV (human papillomavirus) co-infected women. METHODS: Cervical biopsies of 36 patients were assayed by immunohistochemistry, and the Ventana Benchmark System was used for HIV-nef detection. RESULTS: Cervices from HIV-positive patients exhibited nef in cells mainly around blood vessels, and showed a decreased expression of all the immune factors tested except IL10R and STAT3, while RANTES (5.54 cells/mm(2)) was highly expressed in comparison with controls (1.41 cells/mm(2), p = 0.028). COX1 was decreased in the HIV/HPV- (0.32 cells/mm(2), p = 0.017) and HPV-infected patients (0.21 cells/mm(2), p = 0.015) compared with controls (3.28 cells/mm(2)). CONCLUSIONS: It is suggested that RANTES in HIV/HPV co-infection may influence the development of CIN leading to progression to cervical cancer.
Subject(s)
HIV Infections/immunology , HIV-1 , Papillomavirus Infections/immunology , Uterine Cervical Dysplasia/immunology , Uterine Cervical Neoplasms/immunology , Adolescent , Adult , Antiretroviral Therapy, Highly Active , Chemokine CCL5/metabolism , Cyclooxygenase 1/metabolism , Disease Progression , Female , HIV Infections/complications , HIV Infections/drug therapy , Humans , Immunoenzyme Techniques , Middle Aged , Neoplasm Proteins/metabolism , Papillomavirus Infections/complications , Uterine Cervical Neoplasms/pathology , Uterine Cervical Neoplasms/virology , Uterine Cervical Dysplasia/pathology , Uterine Cervical Dysplasia/virologyABSTRACT
The purpose of this study was to look for associations between a newly described class of suppressors of cytokine signaling (SSI/SOCS) and cytokine expression in the uterine cervix from HIV/HPV coinfected women. We examined the pro-inflammatory cytokines TNF-alpha and IL-6 since their expressions are linked and responsible for many aspects of both localized and systemic inflammatory responses. Further, expression of SSI/SOCS has been implicated in the negative feedback regulation of cytokine receptor signaling. PCR-amplified HIV-1 cDNA was noted mainly in the stroma, showing a perivascular distribution, and most of the infected cells colabeled with the macrophage marker CD68. The distribution of IL-6 and TNF-alpha was in the same area to HIV-1 and much greater than normal cervices from women with no evidence of viral infection. SOCS/SSI-1 and -3 mRNA positive cells in the uterine cervix were commonly detected in these noninfected cervical tissues; however, very few cells that contained SOCS were evident in areas where HIV-1, TNF-alpha, and IL-6 expressing cells were found. This suggests that viral-related suppression of SOCS/SSI-1-3 expression may be a factor in the marked local enhancement of TNF-alpha and IL-6 production which, in turn, may help facilitate viral spread; however, further studies should be done in order to elucidate the exact mechanisms of SOCS in the cervix.
Subject(s)
Cervix Uteri/metabolism , HIV Infections/metabolism , Interleukin-6/metabolism , Papillomaviridae , Papillomavirus Infections/metabolism , Suppressor of Cytokine Signaling Proteins/metabolism , Tumor Necrosis Factor-alpha/metabolism , Adult , B7-2 Antigen/genetics , B7-2 Antigen/metabolism , Cervix Uteri/immunology , Cervix Uteri/pathology , Cytokines/genetics , Cytokines/metabolism , DNA, Viral/analysis , Female , HIV Infections/complications , HIV Infections/immunology , HIV-1/isolation & purification , Humans , Interleukin-6/genetics , Papillomaviridae/isolation & purification , Papillomavirus Infections/complications , Papillomavirus Infections/immunology , RNA, Messenger/analysis , RNA, Messenger/metabolism , Reverse Transcriptase Polymerase Chain Reaction/methods , Suppressor of Cytokine Signaling Proteins/genetics , Tumor Necrosis Factor-alpha/geneticsABSTRACT
Foram estudadas 42 amostras de fígado de camundongos inoculados com cercárias do Schistosoma mansoni, obtidas 40, 60, 80 e 120 dias após a infecçäo e processadas rotineiramente. As lâminas obtidas foram coradas pela HE para análise qualitativa e morfométrica do número e área dos granulomas e pelo MGP para quantificaçäo de células apoptóticas. Os animais com 40 dias de inoculaçäo possuíam menos granulomas/lâmina (X=11,78ñ4,01), com áreas pequenas (X=52.713,88ñ5.244,34mm2) e as menores médias de apoptose (X=7,50ñ0.99). Os animais com 60 dias de inoculaçäo tiveram os maiores granulomas (X=114.851,20ñ5.517,20mm2), em maior número X=92,88ñ10,62) e freqüente apoptose (X=18,73ñ1,35). Os com 80 dias de inoculaçäo apresentaram diminuiçao no tamanho dos granulomas (X=89.305,57ñ6.162,79mm2), mas grande quantidade deles (X=131,09ñ15,60) e freqüência maior de apoptose (X=19,93ñ1,49). Com 120 dias, a apoptose continuou freqüente (X=19,84ñ1,88), os granulomas eram mais numerosos (X=231,20ñ34,57), porém menores (X=41.556,58ñ2.043,60mm2). A ocorrência de apoptose ajuda a explicar a reduçäo na celularidade e a conseqüente diminuiçäo da área dos granulomas. A apoptose foi confirmada histologicamente pela técnica de "túnel". Assim, a apoptose participa da modulaçäo do fenômeno inflamatório do tipo granulomatoso, reacional à embolizaçäo de ovos do parasito no fígado. Com a evoluçäo da doença, desenvolve-se uma tolerância imunológica aos antígenos do ovo do Schistosoma mansoni, evidenciada morfologicamente pela diminuiçäo da área média dos granulomas e pela maior freqüência de apoptose nas células componentes do granuloma
