Regulation of Expression of Granulocyte-Macrophage Colony-Stimulating Factor in Human Bronchial Epithelial Cells: Roles of Protein Kinase C and Mitogen-Activated Protein Kinases

Abstract

GM-CSF has a major role in the immune and inflammatory milieu of the airway. Airway epithelial cells (AEC) are among the first targets of environmental stimuli and local cytokines, in response to which they can produce GM-CSF. The regulation of GM-CSF is only minimally understood in AEC. We hypothesized that GM-CSF expression in AEC would result from activation of protein kinase C (PKC) and subsequent activation of the extracellular signal-regulated kinase (MAPKerk1/2) pathway, so we investigated signal transduction pathways in human primary culture bronchial epithelial cells (HBECs). TNF-α, IL-1β, and PMA induced the release of GM-CSF in HBECs. The robust response to PMA was not detected in SV40 adenovirus-transformed normal human bronchial epithelial cells (BEAS-2B). PMA and TNF-α stimulation of GM-CSF required activation of PKC (inhibition by staurosporine and bisindolylmaleimide I). GM-CSF expression was up-regulated by a nonphorbol PKC activator, but not by an inactive PMA analogue. PMA-induced GM-CSF production in HBECs did not require a Ca2+ ionophore and was not inhibited by cyclosporin A. Activation of MAPKerk1/2 via PKC was associated with and was required for GM-CSF production induced by PMA and TNF-α. The data demonstrate regulation of GM-CSF in HBECs by PKC pathways converging on the MAPKerk1/2 pathway and further define cell-specific regulation critical for local airway responses.

Differential regulation ofMoraxella catarrhalis-induced interleukin-8 response by protein kinase C isoforms

“…In addition, several studies have demonstrated airway epithelial cell TNF-a responses to be at least partially sensitive to PKC inhibitors. In human bronchial epithelial cells, cigarette smoke-induced, as well as C5a-mediated, IL-8 expression [42] and TNF-ainduced intercellular adhesion molecule-1 expression [43] were blocked by calphostin C, and TNF-a-induced GM-CSF expression was inhibited by the pan-PKC blocker staurosporine [44]. In addition, HEWSON et al [45] reported that PMA-induced expression of the airway mucins MUC5B and MUC5AC by …”

IL-17A stimulates granulocyte colony-stimulating factor production via ERK1/2 but not p38 or JNK in human renal proximal tubular epithelial cells

“…The MAPK family, including ERK 1/2, p38 MAPK, and JNK, has been shown to play a significant role in the mediation of signals triggered by cytokines, growth factors, and environmental stress, and is known to be involved in various cellular functions (2,15,25,30). Here, we demonstrated for the first time that IL-17A, but not IL-17F, induces G-CSF via the activation of ERK1/2, but not of p38 MAPK or JNK, as well as mRNA transcription and protein translation, and synergizes with TNF-␣ and IL-1␤.…”

Tumour necrosis factor‐α induced CD70 and interleukin‐7R mRNA expression in BEAS‐2B cells

“…The results of several studies which have shown expression and mRNA upregulation of MCP-1, GRO-a, -b, -c , IL-6, IL-8, RANTES and GM-CSF after stimulation in BEAS-2B cells can be confirmed. TNF-a mediated induction in BEAS-2B cells has been demonstrated for IL-6 [8][9][10][11], IL-8 [8][9][10]12], GM-CSF [12][13][14][15], RANTES [9,16] and ICAM-1 [17,18]. MCP-1 was found to be upregulated by BECKER et al [7].…”