Doxycycline‐Induced Expression of Transgenic Human Tumor Necrosis Factor α in Adult Mice Results in Psoriasis‐like Arthritis

Tumor necrosis factor α (TNFα) is the prototype of a proinflammatory cytokine that is mainly secreted by activated macrophages, but also by keratinocytes, fibroblasts, and endothelial cells. It plays a key role in activation of immune cells during the acute phase of inflammation, but it also regulates fundamental cell responses such as proliferation, differentiation, and apoptosis (1). When dysregulated, TNFα displays several pathologic activities resulting in the development of acute and chronic pathologies, among which psoriatic arthritis (PsA) and rheumatoid arthritis (RA) are the most prominent (2–4). In addition to attraction and activation of immune cells, TNFα also activates synovial fibroblasts, keratinocytes, and osteoclasts, which in turn, secrete further cytokines, chemokines, and alarmins, thus potentiating a proinflammatory state and tissue damage. Furthermore, the alarmins S100A8 and S100A9 have been shown to act in a concerted manner with TNFα. S100A8 and S100A9 up-regulate TNFα expression and TNFα up-regulates S100A8 and S100A9 expression in a functional feedback loop, and both S100A8 and S100A9 are involved in induction of matrix metalloproteinases (MMPs) (5,6), contributing significantly to inflammation, cartilage damage, and bone resorption (7–9). Considering the great importance of TNFα for the induction and progression of arthritis, it is not surprising that several mouse models overexpressing the TNFα cytokine have been established. The first was generated by Keffer et al in 1991 (10). This transgenic mouse contains the complete genomic sequence of the human TNFα gene. Only the 3′-noncoding region was replaced by the 3′-untranslated region (3′-UTR) of the human β-globin gene. These mice constitutively express the human TNFα cytokine and, 10 weeks after birth, develop a severe form of RA that affects primarily ankle joints. Other transgenic models soon followed. They constitutively express either a human or a mouse TNFα transgene with a deleted or modified 3′-UTR. These transgenic mice, as well as the tristetraprolin-knockout mouse, all developed arthritic diseases of differing severity and allowed the deciphering of many molecular details underlying their development (4,11). However, TNFα-transgenic mice usually also have impaired fertility (12). This dysfunction presents a serious hindrance in crossing them with other animals to gain more insight into the molecular mechanisms of arthritic diseases or other disorders. To overcome this problem, we generated a doxycycline-inducible human TNFα–transgenic mouse (also called an ihTNFtg mouse) in which the expression of the human TNFα gene is under the control of a tetracycline (Tet)–responsive promoter.