Cytokines and Chemokines: The Role of IL-1 and TNF-alpha in Immunity

This report provides a detailed overview of cytokines and chemokines, key signaling molecules in the immune system. It focuses on the IL-1 and TNF-alpha families, exploring their receptors, signaling pathways, and roles in inflammation and immune responses. The report delves into the process of pyroptosis, a form of programmed cell death mediated by gasdermins, highlighting its role in innate immunity and the release of inflammatory cytokines like IL-1β. It discusses the inflammasome complex, its activation by DAMPs and PAMPs, and the subsequent activation of caspases. The report further examines the involvement of various cytokines, including IL-7, in the development of immune cells and the regulation of the immune system. Negative regulators of the IL-1 pathway are also described. Overall, the report offers a comprehensive understanding of the molecular mechanisms underlying cytokine signaling and its significance in both health and disease, emphasizing the importance of these pathways in immune defense and potential therapeutic targets.

CYTOKINES AND CHEMOKINES.
LECTURE 9
Jianjin Shi, Wenqing Gao, and Feng Shao. Pyroptosis: Gasdermin-Mediated Program
Necrotic Cell Death. Trends in Biochemical Sciences. 2017, 42:245-254

IL-1 AND IL-1R FAMILY

Interleukin-1 receptorInterleukin-1 receptor
o Interleukin-1 receptor (IL-1R) is a Cytokine receptors which bind to Interleukin
(IL-1 family) .
o Interleukin-1 is a group of 11 Cytokines which plays a central role in the regula
immune and inflammatory responses.

TIR= Toll/interleukin-1 receptor (TIR) domain
IRAK=Interleukin-1 receptor-associated kinase 1

Toll-Interleukin receptor (TIR) domainToll-Interleukin receptor (TIR) domain
Is an intracellular signaling domain
found in:
1. IL-1 receptors (IL-1R)
2. Toll-like receptors (TLRs)
3. MYD 88
o The similarity between Toll-
like receptors (TLRs)and IL-
1R is not restricted to
sequencehomologysince
these proteins also share a
similar signaling pathway.
Martin M, Wesche H ; Smmary and comparison of the signaling mechanisms of the Toll/interleukin-1 receptor family.BBA,
Volume 1592, Issue 3, 11 November 2002, Pages 265-280

IL-1 receptor-associated kinase 4
IL-1 receptor accessory protein
Negative
Soluble IL-1 receptor antagonist
soluble IL-1 receptor type 2
DAMP=Danger associated membrane proteins; PAMP=Pathogen-associated membrane proteins
IL-8 (endothelial cells, macrophages, DC

Activation and signaling ofIL-1.Release ofIL-1β from monocytes/macrophagesand
neutrophils requires enzymatic processing of its intracellular precursor protein (pr
This step can occur by two different pathways. Caspase-1-mediated cleavage of p
depends on the activation of an intracellular protein complex called the inflamma
(inflammasome-dependent IL-1β activation).The inflammasome is induced by damage-
associatedmolecularpatterns(DAMPs)or pathogen-associatedmolecularpatterns
(PAMPS)such as uric acid crystals,double-stranded DNA (dsDNA)or ATP.Alternatively,
pro-IL-1β can be cleaved by neutrophil-derived serine proteases in a process inde
of inflammasome activation. IL-1α is produced and localized intracellularly (for ex
epithelial cells). In the event of cell necrosis, IL-1α is released and acts as an alarm
and IL-1β bind to IL-1 receptor type 1 (IL-1R1)on target cells,engaging IL-1 receptor
accessory protein (IL-1RAcP) and leading to activation of IL-1 receptor-associated
(IRAK4) and NFκB, which, in turn, induce the transcription of IL-1 target genes. So
receptor antagonist (IL-1Ra) and membrane-bound or soluble IL-1 receptor type 2
are negative regulators ofthe IL-1 pathway.dsRNA,double-strand RNA;ILC3,innate
lymphoid celltype 3;MMP, matrix metalloproteinase;PGE2,prostaglandin E2;RANKL,
receptor-activator ofNFκB ligand,also known as TNF ligand superfamily member 11;
TH17, T helper 17.

NLRP= nucleotide-binding domain, leucine-rich repeat Protein
NLRC= NLR family CARD domain-containing protein 4
GSDMD Executes Inflammatory Caspases-Induced Pyroptosis by Generating Pores on the Plasma Membrane. The canonical inflammasome sensors
diverse microbial signals and activate caspase-1 through the ASC or NLRC4 adaptor. Caspase-4, 5, and 11 are activated by direct binding to LPS. A
caspase-1 and caspase-11/4/5 cleave GSDMD within the linker between its N-terminal gasdermin-N (green) and C-terminal gasdermin-C (pink) dom
break the autoinhibitory interactions between the two domains. The released gasdermin-N domain binds to phosphoinositides in the plasma memb
oligomerizes to generate membrane pores of about 12–14 nm in inner diameter. The formation of the pores disrupts the osmotic potential, resultin
swelling and eventual lysis. The pores can also serve as a gate for extracellular release of mature IL-1β. The crystal structure of GSDMA3 and the n
electron microscopy picture of GSDMD pores shown on the upper and lower right,
ASC=Adaptor Protein Apoptosis-Associated Speck-Like Protein Containing CARD (ASC)

Studies on macrophage response to bacterialchallenges in
the 1980s and early 1990s record a form of celldeath that
is now realized to be pyroptosis.This celldeath was often
misregarded as apoptosis because ofthe involvementof
caspase-1. For a long time, pyroptosis was thought to
auxiliary eventto IL-1β secretion,a criticalinflammatory
responsein monocytes.Characterizationof various
inflammasomes has established the paramount impo
of caspase-1 in innate immune defenses.The discovery of
caspase-11 and caspase-4/5 function hasexpanded the
notion of pyroptosismediatorsfrom caspase-1 to the
inflammatorycaspasegroup, which also revealsthat
pyroptosis is not limited to monocytic cells

Identification ofgasdermin (GSDMD)as a pyroptotic substrate of
inflammatorycaspaseshas revolutionizedthe understandingof
pyroptosis.The membrane pore-forming activity in the gasderm
domain ofGSDMD is responsible forpyroptosis execution,which
carries out the necrotic function of pyroptosis.The large gasdermin
family suggests ubiquitous occurrence of pyroptosis in mamm
also prompts a new definition of pyroptosis as gasdermin-me
programmed necrosis. The critical role of GSDMD in innate im
and septic shock is justa startfor appreciating the physiologica
functionsof pyroptosis.Association ofgasdermin mutationswith
various genetic diseases suggests a broad function of pyropt
is likely beyond immune defense.Given the unknown function of
other gasdermins and their mechanism of activation, we are
the tip of the iceberg to understand and appreciate the biolog
pathologicalfunctionsof pyroptosis.Lastly,the pore-forming
mechanism shared by the gasdermin family provides an attra
target for future drug development in translationalstudies, including
drugs for treating sepsis