title: Modulation of Female Genital Tract-Derived Dendritic Cell Migration and Activation in Response to Inflammatory Cytokines and Toll-Like Receptor Agonists.
abstract: HIV transmission across the genital mucosa is a major mode of new HIV infections in women. The probability of infection may be influenced by several factors including recruitment and activation of HIV target cells, such as dendritic cells (DCs) and cytokine production, associated with genital inflammation. We evaluated the role of inflammatory cytokines and TLR signaling in migration and activation of genital tract DCs in the human cervical explant model. Hysterectomy tissues from 10 HIV-negative and 7 HIV-positive donor women were separated into ecto- and endocervical explants, and incubated with inflammatory cytokines (TNF-α, IL-1β, IL-8, MIP-1β) or agonists for TLR4 (LPS), TLR2/1 (PAM3) and TLR7/8 (R848). Migration (frequency) and activation (HLA-DR expression) of myeloid and plasmacytoid DCs and Langerhans cells were measured by flow cytometry. We observed that cytokines, LPS and PAM3 induced activation of migrating myeloid and plasmacytoid DCs. LPS induced a 3.6 fold lower levels of migration of plasmacytoid DCs from HIV-infected women compared with HIV-uninfected women (median activation indices of 2.932 vs 0.833). There was however a 4.5 fold increase in migration of Langerhans cells in HIV-infected compared with HIV-uninfected women in response to cytokines (median activation indices of 3.539 vs 0.77). Only TLR agonists induced migration and activation of DCs from endocervical explants. Hormonal contraception use was associated with an increase in activation of DC subsets in the endo and ectocervical explants. We conclude that inflammatory signals in the female genital tract induced DC migration and activation, with possible important implications for HIV susceptibility of cervical tissues.
authors.affiliation: Centre for the AIDS Programme of Research in South Africa (CAPRISA), University of KwaZulu-Natal, Durban, South Africa.|Institute of Infectious Diseases and Molecular Medicine (IDM), Clinical Infectious Diseases Research Initiative (CIDRI), University of Cape Town, Cape Town, South Africa.
authors.forename: Muki S
authors.initials: MS
authors.lastname: Shey
authors.affiliation: Department of Gynaecology and Obstetrics, Prince Mshiyeni Hospital, Durban, South Africa.
authors.forename: Niren
authors.initials: N
authors.lastname: Maharaj
authors.affiliation: Centre for the AIDS Programme of Research in South Africa (CAPRISA), University of KwaZulu-Natal, Durban, South Africa.
authors.forename: Derseree
authors.initials: D
authors.lastname: Archary
authors.affiliation: Centre for the AIDS Programme of Research in South Africa (CAPRISA), University of KwaZulu-Natal, Durban, South Africa.
authors.forename: Sinaye
authors.initials: S
authors.lastname: Ngcapu
authors.affiliation: Centre for the AIDS Programme of Research in South Africa (CAPRISA), University of KwaZulu-Natal, Durban, South Africa.
authors.forename: Nigel
authors.initials: N
authors.lastname: Garrett
authors.affiliation: Centre for the AIDS Programme of Research in South Africa (CAPRISA), University of KwaZulu-Natal, Durban, South Africa.|Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, United States of America.
authors.forename: Salim
authors.initials: S
authors.lastname: Abdool Karim
authors.affiliation: Centre for the AIDS Programme of Research in South Africa (CAPRISA), University of KwaZulu-Natal, Durban, South Africa.|National Health Laboratory Services, Cape Town, South Africa.|Institute of Infectious Diseases and Molecular Medicine (IDM), Division of Medical Virology, University of Cape Town, Cape Town, South Africa.
authors.forename: Jo-Ann S
authors.initials: JA
authors.lastname: Passmore
mesh_terms: D000328:Adult; D002465:Cell Movement / Q000187:drug effects*; D002584:Cervix Uteri / Q000473:pathology; D016207:Cytokines / Q000009:adverse effects*; D003713:Dendritic Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D005260:Female; D005836:Genitalia, Female / Q000473:pathology*; D015658:HIV Infections / Q000473:pathology; D006801:Humans; D018836:Inflammation Mediators / Q000009:adverse effects*; D051193:Toll-Like Receptors / Q000819:agonists* / Q000378:metabolism
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; D051193:Toll-Like Receptors