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Transcription factor activation and mitogenic synergism in airway smooth muscle cells

¹ Dept of Pharmacology, University of Nebraska Medical Center, Omaha, NE, and ² Dept of Pharmacology, Emory University School of Medicine, Atlanta, GA, USA

CORRESPONDENCE: M.L. Toews, 986260 Nebraska Medical Center, Omaha, NE 68198-6260, USA. Fax: 1 4025597495. E-mail: mtoews@unmc.edu

Keywords: activator protein-1, asthma, growth factors, nuclear factor-B, proliferation, Rho

Received: August 15, 2002
Accepted December 13, 2002

This study was supported by the University of Nebraska Medical Center seed grants to M.L. Toews, a University of Nebraska Emley Fellowship to T.L. Ediger and by research grants HL52810 and HL56107 from the National Heart Lung and Blood Institute to T.J. Murphy.

Simultaneous treatment of human airway smooth muscle (HASM) cells with lysophosphatidic acid (LPA) and epidermal growth factor (EGF) leads to strikingly synergistic stimulation of mitogenesis. The purpose of this study was to explore potential sites for signal integration mediating synergism, focusing on extracellular signal-regulated kinase (ERK) and transcription factors involved in proliferation and inflammation as likely candidates.

Activation of ERK was analysed by immunoblotting. Transcription factor activation was assessed using HASM cells transduced with luciferase reporter gene constructs.

LPA and EGF both activated ERK but had no synergistic effect when combined. LPA and EGF both activated activator protein (AP)-1, cyclic adenosine monophosphate response element-binding protein, nuclear factor of activated T-cells and the serum response element; however, only AP-1 activation exhibited synergism. Activation of the inhibitory guanine nucleotide-binding protein and of ERK signalling pathways were required for most transcription factor responses to LPA. In contrast, nuclear factor (NF)-B was activated by LPA but not EGF and NF-B activation was completely blocked only when Rho was inhibited. Rapid activation of Rho was observed in response to LPA but not to EGF. Importantly, inhibition of Rho selectively blocked synergism in both AP-1 activation and mitogenesis.

In summary, extracellular signal-regulated kinase activation is required for many transcription factor responses to lysophosphatidic acid and epidermal growth factor, however it is not synergistic. Activation of activator protein-1 is synergistic, and Rho activation by lysophosphatidic acid is required for synergism in both activator protein-1 activation and mitogenesis.

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