Bcl-3: A Double-Edged Sword in Immune Cells and Inflammation

Abstract

The NF-κB transcription factor family controls the transcription of many genes and regulates a number of pivotal biological processes. Its activity is regulated by the IκB family of proteins. Bcl-3 is an atypical member of the IκB protein family that regulates the activity of nuclear factor NF-κB. It can promote or inhibit the expression of NF-κB target genes according to the received cell type and stimulation, impacting various cell functions, such as proliferation and differentiation, induction of apoptosis and immune response. Bcl-3 is also regarded as an environment-dependent cell response regulator that has dual roles in the development of B cells and the differentiation, survival and proliferation of Th cells. Moreover, it also showed a contradictory role in inflammation. At present, in addition to the work aimed at studying the molecular mechanism of Bcl-3, an increasing number of studies have focused on the effects of Bcl-3 on inflammation, immunity and malignant tumors in vivo. In this review, we focus on the latest progress of Bcl-3 in the regulation of the NF-κB pathway and its extensive physiological role in inflammation and immune cells, which may help to provide new ideas and targets for the early diagnosis or targeted treatment of various inflammatory diseases, immunodeficiency diseases and malignant tumors.

Keywords: Bcl-3; NF-κB; immune cells; immunity; inflammation.

Figure 1

Bcl-3 regulates atypical NF-κB signaling pathways. Bcl-3 acts as a regulator of the atypical NF-κB pathway by binding to processed p50 and p52 homodimers to repress or activate a subset of NF-κB regulated genes. In terms of transcriptional inhibition, Bcl-3 delays the turnover of DNA binding inhibitory p50 homodimer by inhibiting the ubiquitination of p50 homodimer and subsequent proteasome hydrolysis, so as to produce a stable DNA binding complex and inhibit transcription. In addition, the recruitment of co-repressors such as CtBP and HDAC3 may be another mechanism by which Bcl-3 inhibits transcription of NF-κB target genes. In terms of transcriptional activation, Bcl-3 removes repressive p50 homodimers from NF-κB sites, allowing NF-κB heterodimers associated with classical signaling (p65/p50) to activate transcription at these sites. Bcl-3 can also directly transactivate NF-κB-dependent transcription with N-terminal and C-terminal domains by binding to p50 and p52 homodimers. Although Bcl-3 can directly interact with p52 homodimers, the mechanism of Bcl-3 regulating p52 homodimer activation still remains unclear and we speculate that it follows a similar mechanism to that of the p50 homodimers.

Figure 2

Physiological effects of Bcl-3. Bcl-3 is able to participate in cell cycle regulation. On the one hand, it can directly trigger cell division through the activation of cell cycle protein D, thus promoting cell proliferation, and on the other hand, the overexpression of Bcl-3 slows down T cell proliferation at an early stage during the T cell response to antigen. Bcl-3 has been shown to be a survival gene. In immune cells, activated T cells overexpressing Bcl-3 showed increased survival, while T cells lacking Bcl-3 died abnormally. Bcl-3 has been widely defined as an anti-apoptotic gene. One of its anti-apoptotic pathways involves p53 regulation. However, in survival studies of multiple myeloma (MM) cells, overexpression of Bcl-3 increased apoptosis. The cell characteristics that determine whether Bcl-3 promotes or inhibits the transcription of NF-κB-dependent antiapoptotic genes still need to be identified.

Figure 3

Role of Bcl-3 in inflammation. In various disease models, it plays a pro-inflammatory or anti-inflammatory role directly or indirectly in the host's inflammatory response to pathogens by regulating the expression and release of a variety of inflammatory factors.

Figure 4

Bcl-3 as a bidirectional regulator in immune cells. Endogenous Bcl-3 is crucial for the development and function of B cells. For example, Bcl-3 regulates the development of splenic B cells. It limits the development of marginal zone (MZ) B cells but is conducive to the development of follicular (FO) B cells. In addition, Bcl-3 is an environment-dependent T cell response regulator that affects T cell survival, differentiation and proliferation and plays a dual regulatory role in them.