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In this study, we investigated the roles of CD4 T cell cytokines IL-17 and IL-17F in GM-CSF production from lung microvascular endothelial cells (LMVECs). While a wide range of doses of IL-17 or IL-17F alone did not induce GM-CSF release from LMVECs, IL-17 had an enhancing effect on macrophage-derived IL-1β- and TNF-α-induced GM-CSF mRNA expression and production, whereas IL-17F had an enhancing effect on IL-1β-induced GM-CSF production, but a marked inhibitory effect on TNF-α-induced secretion. GM-CSF production was further enhanced with the combination of three cytokines IL-1β, TNF-α and IL-17 or IL-17F. Additionally, when Th1 or Th2 cytokine was combined with IL-1β or TNF-α, both Th1 and Th2 cytokines had a modest stimulatory effect on TNF-α-induced GM-CSF production, whereas IL-4 and IFN-γ profoundly attenuated IL-1β-induced secretion. Moreover, the regulation by IL-17 plus Th1 or Th2 cytokine of GM-CSF production from LMVECs treated with IL-1β or TNF-α was dependent on the concentration of IL-17. Our findings indicate that IL-17 and IL-17F play a differential regulatory role in GM-CSF production by LMVECs stimulated with IL-1β and/or TNF-α, which is sensitive to Th1 and Th2 cytokine modulation. [Copyright &y& Elsevier]

Surfactant protein B (SP-B), a hydrophobic protein of lung surfactant, is essential for surfactant function, normal respiration and survival. SP-B is expressed in a cell-type specific manner by the alveolar type II and bronchiolar (Clara) epithelial cells of the lung and is developmentally induced. Our previous studies showed that the activity of the rabbit SP-B minimal promoter (−236/+39 bp) is dependent on the binding of an array of transcription factors including Sp1, Sp3, thyroid transcription factor 1, hepatocyte nuclear factor 3 and activating transcription factor/cyclic AMP response element binding protein. The SP-B minimal promoter sequence as well as the spacing and orientations of cis-DNA elements are conserved in human, rabbit and mouse SP-B genes. In the present study, we investigated the importance of spacing and orientation of cis-DNA elements on SP-B promoter function in NCI-H441 cells, a human cell line of Clara cell lineage. Further we investigated the effects of transcription factors on SP-B promoter expression by co-transfection experiments. Results showed that disruptions of helical phasing and orientation of cis-DNA elements reduced SP-B promoter activity indicating that proper alignment and orientation of cis-DNA elements are necessary for SP-B promoter function. Co-transfection experiments showed that transcription factors function in a combinatorial rather than in a synergistic manner to enhance SP-B promoter activity. [Copyright &y& Elsevier]