NF-κB in the regulation of epithelial homeostasis and inflammation

Abstract

The IκB kinase/NF-κB signaling pathway has been implicated in the pathogenesis of several inflammatory diseases. Increased activation of NF-κB is often detected in both immune and non-immune cells in tissues affected by chronic inflammation, where it is believed to exert detrimental functions by inducing the expression of proinflammatory mediators that orchestrate and sustain the inflammatory response and cause tissue damage. Thus, increased NF-κB activation is considered an important pathogenic factor in many acute and chronic inflammatory disorders, raising hopes that NF-κB inhibitors could be effective for the treatment of inflammatory diseases. However, ample evidence has accumulated that NF-κB inhibition can also be harmful for the organism, and in some cases trigger the development of inflammation and disease. These findings suggested that NF-κB signaling has important functions for the maintenance of physiological immune homeostasis and for the prevention of inflammatory diseases in many tissues. This beneficial function of NF-κB has been predominantly observed in epithelial cells, indicating that NF-κB signaling has a particularly important role for the maintenance of immune homeostasis in epithelial tissues. It seems therefore that NF-κB displays two faces in chronic inflammation: on the one hand increased and sustained NF-κB activation induces inflammation and tissue damage, but on the other hand inhibition of NF-κB signaling can also disturb immune homeostasis, triggering inflammation and disease. Here, we discuss the mechanisms that control these apparently opposing functions of NF-κB signaling, focusing particularly on the role of NF-κB in the regulation of immune homeostasis and inflammation in the intestine and the skin.

Figure 1

NF-κB regulates immune homeostasis in epithelial tissues. NF-κB displays critical regulatory functions in epithelial cells, where it controls cellular responses to microbial and other environmental factors. NF-κB regulates the expression of cytokines and chemokines by epithelial cells, which act on immune and other non-epithelial cells to modulate immune responses. NF-κB inhibition sensitizes epithelial cells to stress-inducing stimuli coming either from the environment (e.g., microorganisms) or from immune cells (e.g., cytokines) and compromises their viability resulting in the deregulation of tissue immune homeostasis and triggering inflammation. On the other hand, persistently elevated NF-κB activation induces the expression of proinflammatory chemokines and cytokines by epithelial cells that trigger immune cell activation and inflammation. NF-κB activation in immune cells lining epithelial tissues also plays an important role in the regulation of inflammation. NF-κB activation in response to PRR stimulation induces the expression of proinflammatory mediators by myeloid and other immune cells triggering inflammation. Therefore, finely balanced NF-κB activity in both epithelial and immune cells is critical for the maintenance of immune homeostasis and the prevention of chronic inflammation in epithelial tissues.