IL-1 Family Proteins

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IL-1 Family Proteins

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IL-1 Family Proteins Background

The IL-1/IL-1R family of cytokines and receptors

The IL-1 family consists of IL-1α, IL-1β, IL-1 receptor antagonist (IL-1ra), IL-18 and six other family members (IL-1F5-10). Interleukin-1β and IL-18 are the most prominent and well-studied members of this family, sharing ~15% amino acid sequence and having significant similarities in their three-dimensional structures. Interleukin-1β and IL-18 are synthesized as 33 kDa and 24 kDa precursor forms (pro-IL-1β and pro-IL- 18), respectively, that accumulate in the cytosol. However, pro-IL-1β is rapidly induced upon stimulation, whereas proIL-18 is constitutively expressed. Both pro-IL-1β and proIL-18 require caspase-1-mediated proteolytic cleavage into biologically active forms that are released from the cell. Caspase-1 activation requires assembly of a multi-protein complex known as the inflammasome. Inflammasome assembly can be induced upon LPS stimulation, followed by a brief pulse with ATP.

Interleukin-1β is a multifunctional cytokine that plays a crucial role in acute and chronic inflammation. Interleukin-1β is produced by monocytes, macrophages, neutrophils and B cells, amongst other cells, and it affects most cell types in the body, often in concert with TNFα. Inteleukin-1β mediates the expression of potent pro-inflammatory molecules such as iNOS, COX-2, prostaglandins, leukotrienes, chemokines, platelet-activating factor and endothelial adhesion molecules. Due to its potent pro-inflammatory effects, IL-1β plays a vital role in immune processes such as recruitment of immune cells, cell proliferation, tissue damage, induction of fever and septic shock.

Interleukin-18 was first described as an IFNγ inducing factor in the sera of mice injected with heat-killed Propionibacterium acnes and LPS. Today IL-18 is mainly recognized to play a crucial role in Th1 maturation and in the Th1 response. These effects are mediated by its strong IFNγ inducing activity in synergy with IL-12. However, IL-18 is also known to have other functions besides IFNγ induction, such as the induction of Th2 cytokines in the absence of IL-12 and in allergic reactions. Interleukin-18 is mainly produced by monocytes, macrophages, dendritic cells, and epithelial cells, amongst other cell types. Given its pro-inflammatory functions, IL-18 is mainly involved host defense against pathogens, autoimmune diseases, tissue damage, tumor regression mechanisms and septic shock.

The IL-1 and IL-18 receptors (IL-1R and IL-18R) consist of heterodimers (IL- 1R1 and IL-1RAcP; IL-18R and IL-18RAcP), each chain containing an amino-terminal Ig extracellular domain. In their carboxy-terminal cytoplasmic region, IL- 1Rs and IL-18Rs have a TIR domain, which is homologous to the one found in TLRs. Therefore, members of the IL-1R family and TLRs have been categorized into one larger family, namely the Interleukin-1 Receptor/Toll-like Receptor (IL-1R/TLR) superfamily. The TIR domain on IL-1R/TLR family members interacts with TIR domain containing adapter proteins, initiating signaling pathways that culminate in the activation of NFκB and MAPKs.


Regulation of IL-1β and IL-18 biological functions

The naturally occurring inhibitory proteins, IL-1 receptor antagonist (IL-1ra) and IL-18 binding protein (IL-18 BP), respectively, neutralize the biological functions of IL- 1β and IL-18. The IL-1ra is a member of the IL-1 family of cytokines, which shows 26% sequence homology to IL-1β and 18% to IL-1α. IL-1ra binds to the IL-1R, but does not trigger signaling events, thereby preventing IL-1β from binding and signaling through this receptor. IL-1ra can be induced by other cytokines and its levels are increased in autoimmune and inflammatory diseases, suggesting its regulatory role in IL-1-mediated immune responses.

In contrast, IL-18 BP does not belong to the IL-1/IL-1R family and it is a constitutively secreted protein. The IL-18 BP does not have significant amino acid sequence homology with the cell surface expressed IL-18R, therefore it does not represent a product of alternative splicing or a cleaved form of the receptor. Interlukin-18 BP binds IL-18 with high affinity (Kd = 400 pM), neutralizing the IL-18’s IFNγ inducing activity. Interestingly, IFNγ induces IL-18 BP expression as part of a negative feedback loop, which is most likely important in dampening inflammatory responses, which, if uncontrolled, could lead to shock.

Fig. 1 signaling pathways downstream of the IL-1R/IL-18R, TLR4 and TNFR1.


The IL-1R/TLR signaling pathway

Toll-like receptors and IL-1Rs (e.g. IL-1R, IL-18R) share sequence similarity in their cytoplasmic region and are categorized into one superfamily (the IL-1R/TLR superfamily). Therefore, it is not surprising that their downstream signaling pathways are mediated by similar effector molecules.

The TIR domain present in the cytosolic portion of TLRs and IL-1Rs interacts with intracellular TIR domain-containing adaptor molecules. In the case of TLR4, its TIR domain interacts with the adaptor molecule known as TIR-domain-containing adaptor protein (TIRAP) or MyD88-adaptor like (MAL). This interaction allows for recruitment of another TIR domain-containing adaptor molecule known as myeloid differentiation primary-response gene 88 (MyD88). In contrast to TLR4, IL-1Rs interacts directly with MyD88.

The IL-1R and TLR4 pathways are quite similar beyond this point. The main function of MyD88 in both pathways is to recruit members of the IL- 1R-associated kinase (IRAK) family of serine-threonine kinases. Upon stimulation, MyD88 recruits IRAK4 and this allows for association of IRAK-1. IRAK4 then phosphorylates IRAK1 and this allows for recruitment of TRAF6. Phosphorylated IRAK1 and TRAF6 then dissociate from the receptor complex and interact with TGF activated kinase 1 (TAK1), TAK1 binding protein (TAB1) and TAB2. This complex formation induces the phosphorylation of TAB2 and TAK1. IRAK1 then gets degraded and the TRAF6/TAK1/TAB1/TAB2 complex is free to associate with ubiquitin ligases that mediate ubiquitination of TRAF6. Subsequent proteosomal degradation of TRAF6 leads to activation of TAK1. Active TAK1 phosphorylates the IκB kinase (IKK) complex, as well as the MAPKs p38, p42/p44 (ERK1/2), and JNK. The IKK complex then phosphorylates IκB proteins leading to their ubiquitination and degradation. This event leaves NFκB free to translocate into the nucleus and mediate transcription of target primary response genes, which are those that do not require prior de novo protein synthesis for their mRNA expression. NFκB can then act in concert with newly induced proteins (transcription factors and co-factors) to induce the expression of secondary response genes (require prior de novo protein synthesis for their mRNA expression).

Toll-like receptor 4 also associates with the TRIF-related adapter molecules (TRAM), which then associates with the TRIR-domain-containing adapter-inducing interferon-β (TRIF) adapter molecule. This pathway results in the activation of the transcription factors IRF-3 and NFκB and subsequent type I interferon (IFN) production. The latter is known as the MyD88-independent TLR4 signaling pathway. However, production of proinflammatory cytokines, such as IL-1, IL-8, TNF and IL-6, is known to be dependent upon the previously described MyD88-dependent signaling pathway.

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