Transgenic modelling of cytokine polarization in the lung

Abstract

The lung is one of the commonest sites of exposure to environmental allergen or pathogen, so the expression of a variety of cytokines in the lung is dynamically regulated by inflammatory or structural cells in the lung. In the last decades, characterization of the local lung cytokine milieu in allergic or injury models has identified a collective role of certain cytokines, such as type 1 or type 2 cytokines, driving polarized inflammatory and tissue phenotypes. With the development of transgenic mouse modelling systems, the effector function of individual cytokine and the pathophysiological consequences of cytokine polarization in the lung have been effectively evaluated. Here, we present an overview of the transgenic systems currently used to assess the biological function of cytokine or other mediators in the lung. We discuss the inflammatory and tissue phenotypes detected in the lungs of transgenic mice over-expressing representative T helper type 1 (interferon-γ, interleukin-12), T helper type 2 (interleukins -4, -5, -9, -10 and -13), and T helper type 17 cytokines. The effects of genetic modification of cytokine receptors or transcriptional factors such as GATA-3 and T-bet in pulmonary inflammation and remodelling tissue responses are also discussed because these transcription factors are regarded as essential regulators of cytokine polarization. Finally, we discuss the limitations and future application of transgenic approaches in the studies of human lung diseases characterized by cytokine polarization.

Figure 1

Schematic illustration of the constructs used for the generation of lung-specific triple transgenic system. Lung-specific promoters of Clara Cell 10 000 molecular weight (CC10) or surfactant protein-C (SP-C) drive tetracycline-controlled transcriptional silencer (tTS) or tetracycline-controlled transactivator (rtTA) expression in a lung-specific manner. The tetracycline response element (TRE) consisting of tet operon (tetO) and promoter cytomegalovirus (CMV) drive target transgene expression. By simultaneous micro-injection of these three constructs, the expression of transgene can be tightly regulated by the administration of tetracycline (doxycycline; Dox). In the absence of doxycycline, tTS occupies the TRE region of the target construct and prevents the downstream transgene expression. In the presence of doxycycline, rtTA replaces the tTS with greater affinity on the TRE region and activates the transcription of target transgene.