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Inflammation Control through IL-1 Cytokine Family

Chapter 1: Introduction

Background

The body has a first line of defence against molecules that can be pathogenic derived or endogenous danger signals. Besides differentiating between the self and non-self but also differentiates dangerous from the non-dangerous. The immune system also comprises of the inflammation inducing pathogen-associated molecular patterns (PAMPS) that are inclusive of structures that are highly conserved. These are inclusive of the cytosine-phosphate guanine motifs, the heat shock proteins amongst others. Cytokines are important messengers in the immune system. An important group of cytokines are Interleukins that are produced by macrophage, monocytes and lymphocytes. The interleukin-1 cytokine family is a dominant promoter of inflammation and comprise eleven different members (Garlanda et al., 2013). IL-1 is upregulated in response to damage-associated molecular patterns (DAMPs) and pathogen-associated molecular pattern (PAMPs) via Toll-Like Receptor (TLR) activation (Weber et al., 2010). Therapeutic targeting of cytokines may be used to treat immune dysregulation and inflammation (Conaghan, Cook, Hamilton, & Tak, 2019).

The most prevalent members of the IL-1 families are IL-1a and IL-1b and the IL-1 receptor antagonist (IL-1Ra) (Dinarello et al 2012). These molecules are important mediators in many inflammatory syndromes. Basically, cytokines are small proteins that are produced by almost all cells which regulate an affect the body’s immune response. Release of pro-inflammatory cytokines results in the activation of immune cells besides the release of more cytokines. Cytokines can be referred to as interleukins, growth factors or chemokines. They are made up of superfamilies’ that describe similar structures. Distinct cell populations have also been reported to produce similar kinds of cytokines. The impacts of cytokines are dependent on the specific target cell thus making them pleiotropic. Distinct cytokines can be redundant in that they have the same effects on the target cell. Also, they can exhibit synergism. Cytokines have the ability to initiate signal cascades that result in offering the smallest amount of chance to proteins to be detrimental in consequences. Discussed below are the different kinds of cytokines.

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Interleukin 1 family

The first cytokines to be discovered in the family were the interleukin 1 alpha and beta. The two reported to be encoded by distinct genes despite the fact that they can be bound by the same receptor. The interleukin 1 after also has a higher affinity for the receptor 1L1-RI relative to the beta while the latter has a higher affinity for IL-1R2 (Burska et al., 2014). The two interleukins are both translated as 31kDa precursor protein besides being cleaved into minute 17kDa that has distinct amino acid sequences (Clarkson et al., 2019). The precursor of the IL-1α is located intracellularly and is found in many hepatocytes alongside other kind of cells such as the epithelium and he endothelium of the gut. IL-1α is more prevalent in cases of severe infection while low concentrations have been reported in extracellular spaces. Oxidative stress or cytokine exposure by the IL-1 family cytokines makes the expression of IL-1α mRNA to be inducible (Burska et al., 2014).

The effect of post-translational modifications on the activation of IL-1α is yet to be understood. Unlike IL-1β and IL-33, the same biological activity in the induction of IL-6 and TNF in lung cancer cells exist for the precursor form of IL-1α. There exists an organised regulation of the production of IL-1α protein(Clarkson et al., 2019). Besides, the translocation of IL-1α to the nucleus as well as the binding to chromatin takes place during the process of programmed cell death. Pyroptosis induces the leakage of IL-1α in cells that are healthy while the loss of plasma membrane stability explains the release of IL-1α during necrosis (Burska et al., 2014). Inflammation induced programmed cell death results in an improvement of the stability of the cell membrane and its permeability since the inflammasome complex is formed (Garlanda et al., 2013).

IL-1β cytokines are primary sourced from the hematopoietic cells such as the monocytes and the macrophages. They are also secreted by the alpha cells of the pancreases. Epithelium and endothelial IL-1β have also been reported to contribute to cardiovascular disease (Garlanda et al., 2013). The precursor of IL-1β is not as biologically active as that of the alpha interleukin 1 since the activation of IL-1β calls for the proteolytic step through the IL-1β converting enzyme. IL-1β mRNA is induced following the activation of IL-1β or compliment activation due to the activation of the myeloid differentiation primary response in cases of low blood oxygen (Clarkson et al., 2019). The process takes place in the cytosol. DAMP or alarmin molecules can be part of second signals. These bind to the P2 X 7 receptors thus enable the provision of a signal which sees the opening of the potassium channels and thus lowering the levels of potassium in the intracellular fluid (Clarkson et al., 2019). As a result, a process takes place that leads in the formation of pyrin domain-containing protein and apoptosis linked speck like protein with a caspase activation and recruitment domain to the inflammasome complex that improves the permeability of the plasma membrane (Dinarello, 2009). The formation of the complex leads to pro-caspase-1 being activated into caspase-1 then undergoing cleavage to form pro-IL-1β or pro-IL-18 cytokine precursors to their active form. This initiates besides enhancing the pro-inflammatory response (Clarkson et al., 2019). Previous studies have aimed to understand the role that inflammasomes plays in the pathogenesis of infectious and auto inflammatory or autoimmune infections.

Biological functions of interleukin-1

Interleukin-1 has been termed as a potent proinflammatory cytokine that have the abilities of initiating various biological processes that lead to the activation of lymphocytes besides inducing acute-phase hepatic proteins as well as release of leukocytes at the infection location. The interleukin also lead to fever and anorexia (Lie et al., 2012). It is thus very important to the innate immune response of the body. The family are product of macrophages. Apart from the proinflammatory, the interleukin-1α also has normal physiological functions as it takes part in regulation of cell proliferation and differentiation. Studies have also reported that interleukin-1 family signalling often targets the cytoskeleton when there is inflammatory condition in the body as well as in instances of normal tissue haemostasis (Lie et al., 2012).

Interleukin-1 properties and signalling

Interleukin-1 has been noted as the founding member of the interleukin-1 family of ligands that is made up of eleven other members (Lie et al., 2012). The members are inclusive of agonists molecules that have the ability of activating the receptor-mediated signalling as well as the antagonist molecules. Interleukin-1α and interleukin-1β are both termed as IL-1 that were initially reported as the interleukins that are responsible for the induction of fever proinflammatory response (Lie et al., 2012). Besides, the two IL-1 subtypes as well as the physiological inhibitor IL-1Ra are termed as the most examined members of the family.

Biogenesis of IL-1

IL-1 α and IL-1 β are expressed as precursors of 31-kDa and both of them are expressed or encoded with distinct genes (Lie et al., 2012). They are products of macrophages. Through in vitro experiments that us recombinant mature proteins, they have indicated that IL-1α and IL-1β show an expression of same biological effects. However, in vivo, they have been noted to possess distinct biological roles and different regulatory mechanisms. To emphasize, the latter needs to be processed into a protein that is mature to perform optimally (Lie et al., 2012). However, the activity of the former is optimal as both the mature protein as well as the precursor, a property that is owed to the ability of proIL-1α to bind to IL-1 receptor type 1. The precursors that are intracellularly situated are cleaved through the action of cysteine proteases into a propiece as well as mature 17- kDa protein. proIL-1α is particularly processed by calpain while proIL-1 β is processed by caspase-1 (Lie et al., 2012). The secretion of IL-1 does not adhere to the classical endoplasmic reticulum-golgi route since the two subtypes do not have a signal peptide. For compensation, IL-1 β needs a unity of multi-protein complexes that are referred to as inflammasomes for their maturation and secretion (Lie et al., 2012).

The inflammasomes directs the activation of caspase-1, which is essential in the cleavage of proIL-1 β. Assembly of inflammasomes, is initiated by ether infections, stress, or reactive oxygen species as well as cell disruption on certain instance. Besides, their activation is associated with diseases such as type II diabetes and gouts (Lie et al., 2012). Various prototypical inflammasomes are in existence and they all have NOD-like receptors. The NOD-like receptor proteins are termed as pathogens sensors intracellularly and thus enhance the collection of inflammasomes such as the adaptor protein ASC as well as the effector procaspase-1 besides inflammatory caspase that are inclusive of caspase-5 and caspase-11 (Lie et al., 2012). Activation of procaspase-1 also needs a secondary initiator such as P2x7 receptor that results in ionic perturbations in cells (Lie et al., 2012).

Release of mature IL-1 β from cells is a process that is carried out by two different routes (Lie et al., 2012). The first pathway involves the exocytosis of IL-1 β that entails the loading of proIL-1 β as well as the procaspase-1 into the secretory lysosomes thus leading to the externalization of mature IL-1 β alongside other contents of the lysosome (Lie et al., 2012).

Secondly, IL-1 β can also be secreted through the budding of minute plasma membrane blebs and the process has been evidenced in active monocytes that are basically contain bioactive IL-1 β that are released from the plasma membranes (Lie et al., 2012). This occurs after 3′-O-(4-benzoylbenzoyl) ATP (BzATP) is exposed. This is a synthetic P2X7 receptor agonist. As for IL-1α, its detection in the body fluids during inflammation is usually not easy (Lie et al., 2012). This is tied to the fact that it is majorly released by cells that are dying.

Receptor mediated IL-1 signalling

Two types of receptors bind the IL-1 family of cytokines. These are termed as the type I and type II. Signalling of the family is primarily controlled by the IL-1RI (Lie et al., 2012). This is a member of the interlukin-1 receptor superfamily (Lie et al., 2012). On the other hand, the IL-1RII is a prototypical decoy that functions as a regulator. The co-receptor is recruited by the combination of the interleukin and its receptor and the co-receptor is referred to as the IL-1 receptor accessory protein (IL-1RAcP). Its release leads to the formation of heterodimeric receptor complex,which is important in the IL-1RI signal transduction (Lie et al., 2012). The signalling of the receptor begins through the juxtaposition of Toll-IL-I receptor that is situated within the cytoplasmic tails of IL-IRI as well as the IL-1 receptor accessory protein. After these events, myeloid differentiation primary response gene 88 is recruited and it leads to the recruitment of IL-1 receptor associated kinases (IRAKs) (Lie et al., 2012). The dissociation of the kinases then activate nuclear factor- κB (NF-κB) as well as MAPK pathways. TIR domain is not processed by ILRII thus the heterodimeric receptor complex that is produced does not lead to signalling (Lie et al., 2012). Besides, it needs the activity of proIL-1α in the nucleus for its biological process to take place.

The figure below illustrates the receptor mediated IL-1 signalling

the receptor mediated IL-1 signalling

Interleukin-1 and diseases

Interleukin-1 has the ability to increase the concentration of the molecules such as platelet-activating factor as well as prostaglandins through the shock that it induces. The molecules that it releases are termed as potent vasodilators thus induce shock. Blockade of the action of IL-1 leads to the prevention of not only the synthesis but also the release of these mediators. The blockade prevents detrimental biological effects without interrupting the production of molecules that are important in haemostasis. The family of interleukins has been associated with various kinds of infections as discussed below.

Rheumatoid Arthritis

In Rheumatoid Arthritis, IL-1 family of cytokines presents in the synovial lining as well as the synovial fluids of patients that suffer from rheumatoid arthritis. Explants of synovial tissue form rheumatoid arthritis patients also produce IL-I intracellularly. When IL-1 are intraarticularly injected into the body, they initiate leukocyte infiltration as well as breakdown of cartilage besides remodelling of the bones. IL-1 also triggers the expression of bone as well as cartilage cells besides initiating phospholipases and cyclooxygenases and leads to blockade of their actions through a reduction of bacteria-cell-wall induced arthritis.

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