Biochemical Society Transactions

Resolution of Inflammatory Responses: Signalling Networks and Novel Therapeutic Strategies

IKKα in the regulation of inflammation and adaptive immunity

T. Lawrence, M. Bebien


Inflammation is a beneficial response to insult or injury which plays an important role in orchestrating the adaptive immune response. The resolution of acute inflammation is an active process that involves the release of anti-inflammatory mediators and the termination of pro-inflammatory signalling pathways coincident with leucocyte apoptosis and phagocytic clearance and the migration of antigen-presenting cells from the site of inflammation to the local lymphatic tissue. The latter process is required for the development of adaptive immunity and immunological memory. The NF-κB (nuclear factor κB) pathway is an important regulator of inflammation and immunity; NF-κB activation is controlled by IKK [IκB (inhibitor of NF-κB) kinase] complex, which regulates NF-κB activation in response to pro-inflammatory stimuli. The IKK complex has two catalytic subunits, IKKα and IKKβ; recent research shows that these highly homologous kinases have distinct roles in inflammation and adaptive immunity. Here, we discuss the emerging roles for IKKα in the tight regulation of inflammation and the development of adaptive immune responses.

  • adaptive immunity
  • chemokine
  • dendritic cell (DC)
  • inflammation
  • inhibitor of nuclear factor κB kinase (IKK)
  • nuclear factor κB (NF-κB)

Resolution of inflammation

The inflammatory response requires co-ordinated activation of various signalling pathways that regulate the expression of pro-inflammatory mediators and recruitment of leucocytes; inflammation also has an important role in priming the adaptive immune response to generate immunological memory. Deregulation of this complex pathophysiological process may lead to chronic inflammation or inappropriate priming of adaptive immunity and autoimmune disease [1,2]. The NF-κB (nuclear factor κB) pathway has been strongly implicated in the pathogenesis of both chronic inflammatory diseases and autoimmune disease. NF-κB appears to play a pleiotropic role in immune and inflammatory responses; however, the recent description of a second, evolutionarily conserved, NF-κB pathway has revealed new insights into the regulation of NF-κB activation and the role of this pathway in innate and adaptive immunity.


NF-κB is a generic term for a family of transcription factors that play pivotal roles in inflammation and immunity [3], NF-κB consists of various dimers of Rel family proteins; RelA, c-Rel (the product of the cellular homologue of the avian-reticuloendotheliosis-virus transforming gene), RelB, p50 and p52 (expressed as precursor p105 and p100 respectively). Recent research has uncovered two separate pathways for NF-κB activation: the ‘canonical’ pathway is triggered by microbial products and pro-inflammatory cytokines such as TNFα (tumour necrosis factor α) and leads to activation of RelA–p50 dimers; the ‘alternative’ NF-κB pathway [4] is activated by TNF-related cytokines Ltβ (lymphotoxin β) [5], CD40L (CD40 ligand) [4] and RANKL (receptor activator of NF-κB ligand) [6], but not TNFα [7], and results in activation of RelB–p52 NF-κB dimers [8] (Figure 1). These transcription factors are held inactive in the cytoplasm of resting cells by IκB (inhibitor of NF-κB) proteins; the activation of NF-κB is regulated by IKK (IκB kinase) that consists of three subunits: IKKα (IKK1), IKKβ (IKK2) and IKKγ [NEMO (NF-κB essential modulator)]. Upon activation, IKK phosphorylates IκBs promoting proteasome-mediated degradation and release of NF-κB to the nucleus [3]. IKKβ regulates activation of the ‘canonical’ pathway in response to pro-inflammatory cytokines and microbial products through phosphorylation of IκBα releasing RelA–p50, whereas IKKα regulates the ‘alternative’ pathway through the phosphorylation and processing of p100 releasing RelB–p52 complexes [9]. Ample evidence from gene disruption studies indicates that IKKβ is required for inflammation and innate immunity, while IKKα plays an important role in lymphoid organogenesis and adaptive immunity [8,10].

Figure 1 Schematic diagram of the ‘canonical’ and ‘alternative’ NF-κB pathways

TNFα, IL-1β (interleukin 1β) and LPS (lipopolysaccharide) activate IKKβ-dependent phosphorylation of IκBα which is degraded releasing RelA–p50 heterodimers to the nucleus; this pathway regulates proinflammatory and anti-apoptotic gene expression. The ‘alternative’ pathway, triggered by CD40L, RANKL and Ltβ, activates IKKα-mediated phosphorylation of p100 which is processed to p52, releasing RelB–p52 heterodimers to the nucleus which regulate lymphoid organogenesis and adaptive immunity. NIK, Nck-interacting kinase; TLR, Toll-like receptor; Ub, ubiquitin.

IKKα in inflammation and adaptive immunity

The IKK complex required for IκBα phosphorylation consists of two catalytic subunits, IKKα and IKKβ, and the structural subunit IKKγ. Gene disruption studies have shown that only IKKγ and IKKβ subunits are required for IκBα phosphorylation and ‘canonical’ NF-κB activation [10,11]. However, the ‘alternative’ NF-κB pathway, which is characterized by the inducible phosphorylation and processing of p100 to p52, is independent of IKKγ and IKKβ and only requires the IKKα subunit [4,8]. This poses the question of why does the IKK complex contain IKKα? We have addressed this question using transgenic mice that express a mutant form of IKKα, where two serine residues in the activation loop of the kinase have been mutated to alanine (IKKαAA) [12], therefore cells express a native IKK complex but lack the inducible activity of IKKα. Using these mice, we recently described a new role for IKKα in the resolution of acute inflammation by regulating the stability, and promoter recruitment, of RelA- and c-Rel-containing NF-κB complexes [13]. We showed that IKKα activation limits the inflammatory response to bacteria in vivo and inhibits activation of NF-κB in primary macrophages in vitro. IKKαAA macrophages were resistant to pathogen-induced apoptosis, due to elevated expression of anti-apoptotic genes, and showed increased expression of pro-inflammatory cytokines. This anti-inflammatory role for IKKα was independent of p100 processing and the ‘alternative’ NF-κB pathway. Subsequent studies have also shown that IKKα negatively regulates ‘canonical’ NF-κB activation in both Ikkα−/− mouse macrophages [14] and zebrafish with a targeted mutation in the mammalian IKKα orthologue [15]. Ikkα−/− macrophages derived from foetal liver stem cells showed increased expression of pro-inflammatory cytokines and an enhanced ability to stimulate T-cell proliferation [14]. However, interpretation of these studies may be clouded by the use of Ikkα−/− cells; these experiments showed elevated IKKβ activity towards IκBα, which is not seen in cells from IKKαAA mice [12,13]; one would presume that the absence of IKKα protein generates an IKKβ homodimer with increased activity towards IκBα and therefore the context of these experiments is less physiological than those performed with IKKαAA cells.

It is interesting that studies with RelB-deficient mice have also suggested an anti-inflammatory role for RelB [16,17], although this has not been connected with IKKα activity, suggesting other components of the ‘alternative’ NF-κB pathway may have anti-inflammatory functions. RelB-deficient mice die of multiorgan inflammation [16]; this phenotype has been attributed to the breakdown of immunological tolerance due to abnormal development of the thymus; indeed, the pathology in Relb−/− is driven by autoreactive T-cells. However, Relb−/− fibroblasts show increased expression of pro-inflammatory cytokines and chemokines upon stimulation with LPS (lipopolysaccharide) in vitro [17]. A more recent study has also shown that RelB has a role in endotoxin (LPS)-induced tolerance [17], again suggesting components of the alternative pathway have an anti-inflammatory role. The mechanism by which RelB confers this anti-inflammatory effect is not clear; work from David Lo and co-workers suggests that RelB regulates IκBα stability and therefore limits NF-κB activation [18]; more recent work suggests that RelB may negatively regulate canonical NF-κB complexes in the nucleus through protein–protein interactions with RelA [19]. Other work has described the reciprocal recruitment of RelA and RelB to NF-κB target gene promoters; the replacement of RelA-containing dimers with RelB complexes results in the down-regulation of certain NF-κB target genes [20]. The physiological significance of these putative mechanisms has not been established in vivo.

Genetic ‘knockout’ of several components of the ‘alternative’ pathway, including RelB and p52, has established an important role in lymphorganogenesis [8]. Analysis of IKKαAA mice [4,9], and adoptive transfer of IKKα-deficient haemopoietic cells to lethally irradiated mice [21], show an important role for IKKα in the organization of the spleen marginal zone and germinal centre reaction in response to antigenic challenge, indicating an important role of the ‘alternative’ pathway in humoral immunity. The role of IKKα in lymphoidorganogenesis is attributed to its role in Ltβ signalling in spleen stromal cells [8,9]. Ltβ-mediated induction of organogenic chemokines CCL19 (CC chemokine ligand 19), CCL21 and CCL22 is dependent of IKKαmediated activation of RelB–p52 DNA-binding complexes [9]. IKKα has also been described to have a role in B-cell maturation [4], and recent studies have shown that this may contribute to the pathogenesis of B-cell mediated autoimmunity [22]. Our studies have also established that IKKα is required for the generation of cell-mediated immune responses, independent of humoral immunity, such as the DTH (delayed type hypersensitivity) reaction in mice (T. Lawrence, unpublished work). This suggests that IKKα may regulate both humoral and cell-mediated adaptive immune responses. Studies of RelB- and p52-deficient mice have established an important role for these proteins in DC (dendritic cell) function and the generation of cell-mediated immune responses [2327] but the role of IKKα in DC function and maturation has not been examined; however, recent studies have shown that Ltβ signalling is important to maintain DC populations in vivo [28]. The function of IKKα in organogenic chemokine production may also be important in the homing of antigen-loaded DCs to secondary lymphoid tissues where they may prime naïve T-cells, or alternatively the homing of antigen-specific T-cells could be dysregulated in the absence of these chemokines. The role of IKKα in adaptive immunity may well stretch beyond its role in stromal cells and the regulation of lymphoidorganogenesis.

These recent studies suggest that IKKα has evolved opposing, but possibly complementary, roles in acute inflammation and adaptive immunity. IKKα functions to promote the resolution of acute inflammation, by switching off the ‘canonical’ NF-κB pathway, but regulates the development of adaptive immunity through the ‘alternative’ pathway. Although innate immunity is classically considered to prime the adaptive response, for example through promoting DC maturation and migration to local lymphoid tissue, acute inflammation must be switched off to avoid tissue injury [1] while maintaining the development of adaptive immunity (Figure 2). Considering the unique role for DCs in ‘bridging’ innate and adaptive immunity, cross-talk between the ‘alternative’ and ‘canonical’ NF-κB pathways in DCs may regulate the transition from acute inflammation to antigen-specific immune responses that drive chronic inflammatory diseases such as RA. Ultimately, inhibition of IKKα may represent a new therapeutic target to prevent autoimmune inflammation while maintaining innate immunity.

Figure 2 Schematic diagram showing the interaction between acute inflammation and adaptive immunity

Inflammation triggered by activation of resident macrophages (M) and recruited neutrophil phagocytes (P) activates immature DCs (iDC), which take up antigen (Ag) with high efficiency. Cytokines and microbial products promote DC maturation and migration to lymphatic tissue, regulated by specific chemokines such as CCL19 [ELC (Epstein–Barr virus-induced receptor ligand chemokine)], CCL21 [SDF-1 (stromal-derived factor 1)] and CCL22 [MDC (macrophage-derived chemokine)]. Mature DCs (mDC) up-regulate co-stimulatory molecules and antigen presentation to prime the specific immune response. IKKα switches off expression of TNFα, IL-6 and IL-12 in macrophages [13], but positively regulates the production of organogenic chemokines such as CCL19 and CCL21 [9]. We hypothesize that IKKα limits the duration of acute inflammation and promotes development of adaptive immunity.


  • Resolution of Inflammatory Responses: Signalling Networks and Novel Therapeutic Strategies: Biochemical Society Focused Meeting held at Wolfson Conference Centre, Hammersmith Hospital, London, U.K., 6 October 2006. Organized and Edited by I. Adcock and P. Evans (National Heart and Lung Institute, Imperial College London, U.K.).

Abbreviations: CCL19, CC chemokine ligand 19; CD40L, CD40 ligand; DC, dendritic cell; NF-κB, nuclear factor κB; IκB, inhibitor of NF-κB; IKK, IκB kinase; IL, interleukin; LPS, lipopolysaccharide; Ltβ, lymphotoxin β; RANKL, receptor activator of NF-κB ligand; TNFα, tumour necrosis factor α


View Abstract