Abstract
Administration of glucocorticoids and caffeine is a common therapeutic intervention in the neonatal period, but possible interactions between these substances are still unclear. The present study investigated the effect of caffeine and different glucocorticoids on expression of surfactant protein (SP)-B, crucial for the physiological function of pulmonary surfactant. We measured expression levels of SP-B, various SP-B transcription factors including erythroblastic leukemia viral oncogene homolog 4 (ErbB4) and thyroid transcription factor-1 (TTF-1), as well as the glucocorticoid receptor (GR) after administering different doses of glucocorticoids, caffeine, cAMP, or the phosphodiesterase-4 inhibitor rolipram in the human airway epithelial cell line NCI-H441. Administration of dexamethasone (1 µM) or caffeine (5 mM) stimulated SP-B mRNA expression with a maximal of 38.8±11.1-fold and 5.2±1.4-fold increase, respectively. Synergistic induction was achieved after co-administration of dexamethasone (1 mM) in combination with caffeine (10 mM) (206±59.7-fold increase, p<0.0001) or cAMP (1 mM) (213±111-fold increase, p = 0.0108). SP-B mRNA was synergistically induced also by administration of caffeine with hydrocortisone (87.9±39.0), prednisolone (154±66.8), and betamethasone (123±6.4). Rolipram also induced SP-B mRNA (64.9±21.0-fold increase). We detected a higher expression of ErbB4 and GR mRNA (7.0- and 1.7-fold increase, respectively), whereas TTF-1, Jun B, c-Jun, SP1, SP3, and HNF-3α mRNA expression was predominantly unchanged. In accordance with mRNA data, mature SP-B was induced significantly by dexamethasone with caffeine (13.8±9.0-fold increase, p = 0.0134). We found a synergistic upregulation of SP-B mRNA expression induced by co-administration of various glucocorticoids and caffeine, achieved by accumulation of intracellular cAMP. This effect was mediated by a caffeine-dependent phosphodiesterase inhibition and by upregulation of both ErbB4 and the GR. These results suggested that caffeine is able to induce the expression of SP-transcription factors and affects the signaling pathways of glucocorticoids, amplifying their effects. Co-administration of caffeine and corticosteroids may therefore be of benefit in surfactant homeostasis.
Highlights
Pulmonary surfactant is a complex mixture of 90% lipids and 10% proteins lining the inner epithelium of the alveoli, thereby stabilizing the surface of the air-blood barrier and improving gas exchange [1]
The highest stimulation was achieved using 1 mM dexamethasone together with 10 mM caffeine, leading to 206659.7-fold significantly higher levels of surfactant protein (SP)-B mRNA compared to untreated cells and 167627.4-fold significantly higher levels if compared to cells treated with 1 mM dexamethasone (Fig. 1C)
Since the biological effects of glucocorticoids are mediated by their binding to the glucocorticoid receptor (GR), a ligand-activated transcription factor belonging to the steroid/thyroid hormone receptor superfamily, we investigated whether dexamethasone and caffeine were able to affect GR mRNA expression
Summary
Pulmonary surfactant is a complex mixture of 90% lipids and 10% proteins lining the inner epithelium of the alveoli, thereby stabilizing the surface of the air-blood barrier and improving gas exchange [1]. After maturation from proproteins, the hydrophobic proteins SP-B and SP-C are stored together with the lipid fraction in the so called lamellar bodies and are secreted onto the alveolar surface [3]. SP-B itself promotes the formation and stability of the surfactant monolayer through its interactions with dipalmitoyl phosphatidylcholine and is mainly synthesized in alveolar type II and Clara cells, the main producers of surfactant [5]. Various other transcription factors, like jun B proto-oncogene (Jun B), jun proto-oncogene (cJun), Sp1 transcription factor (SP1), Sp3 transcription factor (SP3), hepatocyte nuclear factor 3-a (HNF-3a), and cAMP response element binding
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