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Abstract
A proper inflammatory response is critical to the restoration of tissue homeostasis after injury or infection, but how such a response is modulated by the physical properties of the cellular and tissue microenvironments is not fully understood. Here, using H358, HeLa, and HEK293T cells, we report that cell density can modulate inflammatory responses through the Hippo signaling pathway. We found that NF-κΒ activation through the proinflammatory cytokines interleukin-1β (IL-1β) and tumor necrosis factor α (TNFα) is not affected by cell density. However, we also noted that specific NF-κΒ target genes, such as cyclooxygenase 2 (COX-2), are induced much less at low cell densities than at high cell densities. Mechanistically, we observed that the transcriptional coactivators Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) are localized to the nucleus, bind to TEA domain transcription factors (TEADs), recruit histone deacetylase 7 (HDAC7) to the promoter region of COX-2, and repress its transcription at low cell density and that high cell density abrogates this YAP/TAZ-mediated transcriptional repression. Of note, IL-1β stimulation promoted cell migration and invasion mainly through COX-2 induction, but YAP inhibited this induction and thus cell migration and invasion. These results suggest that YAP/TAZ-TEAD interactions can repress COX-2 transcription and thereby mediate cell density-dependent modulation of proinflammatory responses. Our findings highlight that the cellular microenvironment significantly influences inflammatory responses via the Hippo pathway.
Highlights
A proper inflammatory response is critical to the restoration of tissue homeostasis after injury or infection, but how such a response is modulated by the physical properties of the cellular and tissue microenvironments is not fully understood
We examined its effect on the NF-B signaling pathway by plating cells at different cell densities and stimulating them with IL-1 or TNF␣
We found that short interfering RNAmediated knockdown of Yes-associated protein (YAP)/transcriptional coactivator with PDZ-binding motif (TAZ) or large tumor suppressors 1 (LATS1)/2 did not affect the activation of either ERK1/2 or the NF-〉 pathways stimulated by IL-1 because the pattern of ERK activation, IB␣ degradation and resynthesis, and A20 induction were similar among the control siRNA, siYAP/TAZ, and siLATS1/2 groups (Fig. 2A and Fig. S2A)
Summary
A proper inflammatory response is critical to the restoration of tissue homeostasis after injury or infection, but how such a response is modulated by the physical properties of the cellular and tissue microenvironments is not fully understood. We noted that specific NF-〉 target genes, such as cyclooxygenase 2 (COX-2), are induced much less at low cell densities than at high cell densities. IL-1 stimulation promoted cell migration and invasion mainly through COX-2 induction, but YAP inhibited this induction and cell migration and invasion These results suggest that YAP/TAZ–TEAD interactions can repress COX-2 transcription and thereby mediate cell density– dependent modulation of proinflammatory responses. More than 200 genes are known to be activated by NF-〉, including chemokines, cytokines, adhesion molecules, inflammatory mediators, apoptosis inhibitors, and others [10]. These genes perform a variety of essential functions. Modulation of inflammatory responses by YAP/TAZ an inducible isozyme that catalyzes the first step in the synthesis of prostanoids, mediates an effective inflammatory response, whereas negative regulators of the NF-〉 signaling pathway (such as IB␣ and deubiquitinating enzymes A20 and CYLD) help resolve inflammation and reset the response to latency [11, 12]
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