Koh Nakata

Differentiation of Monocytes to Macrophages Switches the Mycobacterium tuberculosis Effect on HIV-1 Replication from Stimulation to Inhibition: Modulation of Interferon Response and CCAAT/Enhancer Binding Protein β Expression

HIV-1 replication is inhibited in uninflamed lung macrophages and is stimulated during tuberculosis. Attempts to recapitulate activation of HIV-1 replication in primary monocytes and macrophages ex vivo and in the untreated and PMA-treated THP-1 cell line model in vitro have produced opposite results depending on the state of differentiation of the cells. After infection with Mycobacterium tuberculosis, monocytes enhanced HIV-1 replication and produced a stimulatory 37-kDa CCAAT/enhancer binding protein β (C/EBPβ) transcription factor, whereas macrophages suppressed HIV-1 replication and produced an inhibitory 16-kDa C/EBPβ transcription factor. IFN-β induced inhibitory 16-kDa C/EBPβ in macrophages, but had no effect on C/EBPβ expression in monocytes. Macrophages, but not monocytes, were able to activate IFN-stimulated gene factor-3 (ISGF-3), a transcription factor composed of STAT-1, STAT-2, and IFN regulatory factor (IRF)-9, after infection with M. tuberculosis or stimulation with type I IFN. Macrophages expressed IRF-9 DNA-binding activity, but monocytes did not, and addition of the IRF-9 component reconstituted ISGF-3 in extracts of IFN-treated monocytes. Modulation of IFN responsiveness upon differentiation occurred at least in part through a post-transcriptionally regulated increase in IRF-9 expression. Both monocytes and macrophages maintained IFN responsiveness, activating STAT-1 homodimer formation and transcription of the STAT-1 gene after IFN stimulation. In addition, both monocytes and macrophages were able to activate NF-κB upon infection with M. tuberculosis. These results show that induction of ISGF-3, expression of the inhibitory 16-kDa C/EBPβ, and suppression of HIV-1 replication via a transcriptional mechanism are macrophage-specific responses to infection with M. tuberculosis.

Lungs of patients with idiopathic pulmonary alveolar proteinosis express a factor which neutralizes granulocyte‐macrophage colony stimulating factor

Mice deficient in granulocyte‐macrophage colony stimulating factor (GM‐CSF) develop pulmonary alveolar proteinosis (PAP). We found that bronchoalveolar lavage fluid (BALF) from 11 patients with idiopathic pulmonary alveolar proteinosis (IPAP) suppressed the growth of peripheral blood monocytes and TF‐1 cells, a cell line dependent on either GM‐CSF or interleukin‐3 (IL‐3). The inhibitory effect of PAP‐BALF occurred only when TF‐1 cells were cultured with GM‐CSF but not when cultured with IL‐3, suggesting that PAP‐BALF contains a factor that specifically interferes with GM‐CSF function. 125I‐GM‐CSF binding to TF‐1 cells was prevented in the presence of BALF from IPAP patients. Furthermore, cross‐linking of 125I‐GM‐CSF to IPAP‐BALF produced two major bands on SDS‐PAGE; these bands were not observed in normal BALF. These data suggest that IPAP is caused by expression of binding factor(s) which inhibit GM‐CSF function in the lung.

?? T-cell receptor-positive cells of human skin. II. Appearance in delayed-type hypersensitivity reaction

In order to investigate the distribution and involvement of human γδ T-cell receptor-positive (TCR+) cells in delayed-type hypersensitivity reactions of the skin, we examined the occurrence and kinetics of γδ TCR+ cells during skin reactions of allergic contact dermatitis. In normal human skin sections, γδ TCR+ cells were scarce. In allergic contact dermatitis from DNCB, increased γδ TCR+ cells were observed both in the epidermis and in the dermis from 48 h after the challenge. Most of the γδ TCR+ cells were TCRδ1+ δTCS1− BB3+ TiγA+ (Vδ1− Vδ2+ Vγ9+). The percentage of γδ TCR+ cells in the peripheral blood remained unchanged and a few γδ TCR+ cells in the skin lesions proliferated in situ. It is suggested that the γδ TCR+ cells in skin lesions of allergic contact dermatitis may not be involved in initiation of delayed-type hypersensitivity but may have some other roles responding to factors induced in the reaction.