Molecular control of immune/inflammatory responses: Interactions between nuclear factor-κB and steroid receptor-signaling pathways

Abstract

Immunity and inflammation are physiological processes of profound importance to an organism: without these processes, a host would quickly succumb to invading pathogens or damaging stimuli, yet excessive or inappropriate activation of these responses causes tissue/cellular damage and even death. Therefore, maintaining immune homeostasis is critical for the survival of an organism. Both pro- and antiinflammatory mechanisms must be present and functional for a cell (and by extension, an organism) to survive in the face of environmental stimuli that elicit an immune response. These pathways, when activated simultaneously, provide homeostasis by 'pulling' the cell in opposite directions. Two candidate signaling pathways for this physiological balancing act are the NF-κB and GR-mediated signaling pathways. These pathways, as discussed in this review and depicted in Fig. 6, have important and opposing roles in immune function. NF-κB is a transcription factor which induces the expression of many genes that participate in immune and inflammatory responses, while GR is a transcription factor that serves as a potent antiinflammatory agent and immune suppressor. Their interactions within the cell, while not yet completely understood, appear to be an important, possibly even the primary, mechanism of immune homeostasis. For this reason, research on GR-NF-κB interaction continues to expand as many groups strive to fill in the 'black bones' where the GR and NF-κB-signaling pathways cross. The interaction of inducible/activatable transcription factors, such as NF-κB or the steroid hormone receptors, with the basal transcriptional machinery is an important mechanism for tightly regulating gene-mediated physiological processes such as immunity and inflammation. However, the mechanism by which GR elicits its antiinflammatory effects has, until recently, proven to be a conundrum, since the majority of proimmune/proinflammatory genes repressed by glucocorticoids have no identifiable GREs in their promoters that would allow GR to interact with the basal transcription machinery. The relatively recent discovery that GR and NF-κB are mutual transcriptional antagonists has given researches a handle on potential mechanisms of immune regulation by glucocorticoids. The functional interaction of NF-κB and GR has thus far been demonstrated only in in vitro and cell culture systems, so it is important to consider whether these regulatory factors interact in precisely the same way within a more 'physiological' context. Clearly, the field of NF-κB/GR research must move toward understanding how these two factors interact in an intact animal. However, understanding how such complex and broadly used signaling pathways interact within an intact organism is a daunting task. As discussed in this review, both NF-κB and GR have cell/tissue-specific effects, and both cross-talk with other steroid hormone receptors, transcription factors, and a variety of other cellular signaling cascades that are functioning simultaneously within an animal. The design of tissue-specific transgenic or inducible NF-κB and GR knockout animals would provide a powerful tool for understanding functional interactions of NF-κB and GR in immunity and inflammation (as well as other processes mediated by these two factors) in a more physiological context. Given our present scientific tools, however, the most valuable means of understanding NF-κB/GR cross-talk is probably still to examine the interaction in a relatively artificial context where a single pathway or response can be evaluated. Despite the limitations of currently available model systems, our understanding of the elegant interplay between NF-κB and GRs in terms of immune regulation is rapidly improving. Gaining insight into mechanisms of NF-κB/GR antagonism not only opens up the possibility of novel, transcription-based therapy in immune pathology, but also raises the exciting possibility that NF-κB may also interact with GR or another steroid hormone receptor in other cell types to regulate other important physiological and developmental processes. As the body of research concerning NF-κB/GR expands, we may find that GR/NF-κB antagonism in the immune system is simply the prototype of a fundamental NF-κB/steroid receptor factor cross-talk mechanism that affords tight homeostatic control of critical cellular processes in a variety of cell types. Preliminary studies indicate that NF-κB also interacts with androgen, estrogen, and PRs. These findings suggest that we may find sex-specific differences in immunity or other NF-κB-mediated responses in an organism due to cross-talk with gonadal steroid-mediated signaling pathways. It also suggests the existence of a general nuclear receptor/NF-κB cross-talk mechanism that may exert widespread influence on cell type-specific gene transcription. In light of this possibility, continued research into the mechanism of GR/NF-κB antagonism is truly exciting.