Page 164 - Clinical Immunology_ Principles and Practice ( PDFDrive )

146 ParT ONE Principles of Immune Response

role is to recognize the trigger for activation (whether directly or
indirectly remains unclear); (ii) a portion called a NACHT domain, Interleukin-33
which leads to adenosine triphosphate (ATP)–dependent dimeriza- IL-33 (previously known as IL-1 F11) appears to be a cytokine
tion of the NLR after trigger recognition; and (iii) a protein–protein that acts by binding to a specific extracellular receptor, namely,
interaction domain, most commonly either a pyrin or a CARD the IL-1R –related protein ST2, also known as IL-33R. It also
domain, which recruits caspase-1. acts as a transcriptional repressor by associating with chromatin.
The NLRP3 inflammasome is the best studied. Recognition Because of this dual effect and because of the expression of ST2
of the trigger by NLRP3 causes its dimerization, recruitment of on different cell types, IL-33 acts on both immune and nonim-
ASC via interaction of the pyrin domains of NLRP3 and ASC, mune cells. It acts on T and B cells, promoting Th2-associated
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and subsequent recruitment of caspase-1 via the CARD domains cytokines, including IL-4, IL-5, and IL-13. IL-33 acts on mast
present in both ASC and caspase-1. Dimerization of caspase-1 cells, promoting degranulation, an effect also shown on basophils
upon inflammasome assembly allows for autoactivation by and granulocytes in general, but also enhancing cell survival.
cleavage of the proform to generate active enzyme. The NLRP3 Upon cleavage by mast cell proteases, IL-33 can also activate
inflammasome can be activated by ATP, components of gram- ILC2, inducing cytokines production and eosinophils recruit-
positive bacterial cell walls, intracytoplasmic DNA, molecules ment. 65,66 Interestingly, IL-33–treated basophils have been shown
resulting from tissue damage, uric acid crystals, alum, silica, to suppress arthritic inflammation. IL-33 can also act on
asbestos, and amyloid-β among others. Cigarette smoke and endothelial and epithelial cells to induce angiogenesis and produc-
cholesterol crystals also activate caspase-1. 61 tion of other cytokines and chemokines.
Similar to IL-1α, IL-1β can be cleaved and activated by other
proteases, including neutrophil elastase, cathepsin, and proteinase-3 Interleukin-36
(PR-3). Mast cell proteases, as well as caspase-8, have also been The three members of the IL-36 subfamily, IL-36α, β, and γ, are
shown to cleave IL-1β precursor. The mechanism of release of encoded by separate genes. They bind to a receptor composed
IL-1 and related family members from cells is somewhat mysterious of IL-36R and IL-1RacP. These cytokines are mostly expressed
because they lack a classic signal peptide and do not enter the in skin. IL-36α transgenic mice exhibit skin inflammation, and
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secretory pathway. Although there is some evidence that IL-1β these IL-36 cytokines can play a role in psoriasis. IL-36 receptor
can be cleaved and released from cells without cell death, a large antagonist (IL-36Rα, also known as IL-1 F5) acts as an antagonist
body of evidence suggests that IL-1 family proteins are released for the three IL-36 family cytokines. IL36RA mutations are
from cells upon lysis. Because of this, and the large numbers of associated with generalized pustular psoriasis. Keratinocytes from
cellular insults that result in release of IL-1 and related proteins patients with deficiency of IL-36 receptor antagonist (DITRA)
and trigger inflammation, it has been proposed that they function have elevated levels of multiple inflammatory cytokines in lesional
as “alarmins” and act as sentinels of cellular damage. skin. They are highly expressed in skin and airway and may be
The principal functions of IL-1 include the induction of involved in skin diseases, such as psoriasis (Chapter 64).
acute-phase protein synthesis, cachexia, and fever. In fact, it was
the first endogenous pyrogen to be identified. It induces the Interleukin-37
production of IL-6 and chemokines, promotes hematopoiesis, IL-37 (also known as IL-1 F7) exists in several splice variants of
stimulates adhesion of vascular leukocytes to the endothelium, which IL-1F 7b has been the most studied. IL-37 binds to IL-18Rα
and has procoagulant effects. Importantly, IL-1 is a critical dif- chain, although with a lower affinity than IL-18. It uses TIR8
ferentiation factor for Th17 cells, which underscores the role of (also known as SIGIRR) as second chain of the receptor. Despite
this cytokine in inflammation and inflammatory diseases. binding to the same receptor and its capacity to complex with
Interestingly, it has recently been shown to activate ILC2, inducing IL-18Acp, IL-37 does not seem to act as a receptor antagonist for
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proliferation and cytokine expression. Unlike Fas and some of IL-18. IL-37 translocates to the nucleus and binds Smad3, enabling
the other TNF-family cytokines, IL-1 does not directly induce regulation of gene transcription. Cleavage of IL-37 appears to be
cell death. Mononuclear phagocytes are the main, but not dependent on caspase-1 and -4. Its antiinflammatory activity is
−/−
−/−
exclusive, source of IL-1. IL-1RI and IL-1β mice have blunted dependent on ASC or NLRP3. IL-37 negatively regulates excessive
fever responses to some (but not all) stimuli. This indicates that inflammatory responses. Macrophages expressing IL-37 no longer
despite the impressive actions of IL-1, it is evidently redundant secrete proinflammatory cytokines, and IL-37 transgenic mice
to some extent in febrile responses. are resistant to LPS-induced shock. 68
Interleukin-18 Interleukin-38
A major action of IL-18, which is constitutively expressed by IL-38 (IL-1 F10) has a 43% homology with IL-36Rα and, similarly,
most cell types, is the induction of IFN-γ, and NK cells activation, has an antiinflammatory activity. It is released by apoptotic cells
a function it typically performs synergistically with IL-12. These to limit macrophage activation. Polymorphic IL-38 genes have
functions are important for its antitumor activity. It has also been associated with increased susceptibility for autoimmune
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been shown to promote angiogenesis and tumor progression. and autoinflammatory diseases (e.g., RA, spondyloarthritis, and
IL-18 can induce IL-4 and IL-13 production, indicating a psoriatic arthritis).
somewhat broader range of action. IL-18 precursor can be cleaved
by the NRLP3 inflammasome as well as the NRLC4. IL-18–binding Other Members of the Interleukin-1 Family
protein interacts with IL-18 and prevents association with IL-18R. The remaining members of the IL-1 and IL-1R families are the
IL-18R was first designated IL-1Rrp (IL-1R–related protein) receptor homologues APL and TIGIRR. These receptors have
before being recognized as the receptor for IL-18. The receptor limited tissue distribution, with TIGIRR found almost exclusively
is expressed predominantly on T cells, B cells, and NK cells. It in the brain and APL in the brain and a small number of other
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associates with an accessory protein, IL-18RAcP. tissues. Little is known of about the function of TIGIRR or