ImmunologyTier 1Medical Sciences concept

Interleukin functions (haematopoiesis, inflammation, immune regulation)

Core concept

The three acute-phase monokines - macrophage-derived, and the ones that make a patient sick

IL-1beta - fever (hypothalamic PGE2), adhesion molecule expression, local inflammation; drives IL-6
- Made as inactive pro-IL-1beta, cleaved by inflammasome-activated caspase-1 - the checkpoint that autoinflammatory disease breaks
TNF-alpha - membrane-bound, cleaved by TACE/ADAM17 to soluble; leukocyte egress at the endothelium, vascular permeability, fever, cachexia, shock
IL-6 - *the dominant driver of the hepatic acute-phase response - CRP, fibrinogen, hepcidin, ferritin*
- Also: osteoclast activation, B-cell differentiation and antibody production, Th17 differentiation, thrombocytosis
- CRP is essentially an IL-6 readout - which is why IL-6 blockade abolishes CRP and masks infection

Cytokine profiles define T-helper subsets

Subset	Inducing cytokine	Signature output	Function
Th1	IL-12	IFN-gamma, IL-2, TNF-beta	Macrophage activation, intracellular pathogens, IgG opsonising
Th2	IL-4	IL-4, IL-5, IL-13 (+IL-10)	IgE class switch (IL-4/13), eosinophils (IL-5), helminths, allergy
Th17	IL-6 + TGF-beta, maintained by IL-23	IL-17A/F, IL-22	Neutrophil recruitment, extracellular bacteria and fungi, mucosal defence
Treg	TGF-beta + IL-2	IL-10, TGF-beta	Suppression, tolerance

IL-10 and TGF-beta are the anti-inflammatory pair; IL-10 loss-of-function -> very-early-onset IBD

Key detail

Haematopoietic and immune interleukins worth knowing

Cytokine	Source	Key action
IL-2	Activated T cells	T-cell proliferation; also expands Tregs at low dose - the target of basiliximab and of aldesleukin
IL-3	T cells	Multipotent - drives HSC to myeloid progenitor, upstream of the lineage-specific factors
G-CSF / GM-CSF	Stroma, macrophages	Neutrophil / myeloid lineage output (filgrastim, sargramostim)
IL-5	Th2, ILC2	Eosinophil growth, survival and activation
IL-4	Th2	IgE class switch, Th2 polarisation
IL-13	Th2, ILC2	Mucus, airway remodelling, fibrosis, IgE
IL-6	Macrophage, fibroblast, T cell	Acute phase, Th17, plasma cells
IL-8 (CXCL8)	Macrophage, epithelium	Neutrophil chemotaxis
IL-12	Dendritic cell	Th1 and NK activation (with IL-18 -> IFN-gamma)
IL-15	Monocytes, epithelium	NK and memory CD8 survival; drives intraepithelial lymphocytes in coeliac disease
IL-17A/F	Th17, gamma-delta T	Neutrophil recruitment, antimicrobial peptides
IL-23	Dendritic cell	Maintains the Th17 phenotype - the upstream target in psoriatic disease
IL-31	Th2	Pruritus (nemolizumab)
IL-33, TSLP, IL-25	Epithelial alarmins	Initiate type 2 inflammation upstream of everything (tezepelumab targets TSLP)
IFN-gamma	Th1, NK	Macrophage activation, MHC upregulation
IFN-alpha/beta	pDC, all cells	Antiviral; excess -> the SLE interferon signature

Cytokine receptor families and their shared chains explain the immunodeficiencies and the drugs
- Common gamma chain (IL-2, 4, 7, 9, 15, 21) - mutation -> X-linked SCID; signals via JAK1/JAK3
- IL-4Ralpha is shared by the type I (IL-4) and type II (IL-4 + IL-13) receptors -> dupilumab blocks IL-4Ralpha and therefore blocks BOTH IL-4 and IL-13
- IL-12 and IL-23 share the p40 subunit -> ustekinumab (anti-p40) blocks both; guselkumab, risankizumab, tildrakizumab, mirikizumab target p19 (IL-23 only)

Clinical relevance

Cytokine-directed drugs by target

Target	Drugs	Main uses
TNF	infliximab, adalimumab, etanercept (receptor fusion), golimumab, certolizumab	RA, PsA, AS, IBD, uveitis; screen for latent TB and hepatitis B; avoid in demyelination and moderate-severe heart failure
IL-1	anakinra (IL-1RA), canakinumab (anti-IL-1beta), rilonacept	CAPS, FMF, Still's disease, gout flare, recurrent pericarditis
IL-6 / IL-6R	tocilizumab, sarilumab (IL-6R), siltuximab (IL-6, Castleman)	RA, GCA, CRS after CAR-T, sJIA; abolishes CRP - infection is masked; bowel perforation risk in diverticular disease
IL-5 / IL-5R	mepolizumab, reslizumab; benralizumab (IL-5Ralpha, ADCC-depleting)	Eosinophilic asthma, EGPA, hypereosinophilic syndrome, CRSwNP
IL-4Ralpha	dupilumab	Atopic dermatitis, type 2 asthma, CRSwNP, EoE, prurigo nodularis, COPD with eosinophilia, bullous pemphigoid
IL-13	tralokinumab, lebrikizumab	Atopic dermatitis
TSLP	tezepelumab	Severe asthma regardless of phenotype
IL-12/23 p40	ustekinumab	Psoriasis, PsA, Crohn's, UC
IL-23 p19	risankizumab, guselkumab, tildrakizumab, mirikizumab; oral peptide icotrokinra	Psoriasis, PsA, IBD
IL-17	secukinumab, ixekizumab (IL-17A); brodalumab (IL-17RA); bimekizumab (IL-17A+F)	Psoriasis, PsA, axSpA; *can worsen or precipitate IBD; candidiasis is on-target*
JAK (downstream of many)	tofacitinib, baricitinib, upadacitinib	RA, PsA, UC, atopic dermatitis, alopecia areata; ORAL-Surveillance: MACE, VTE, malignancy signal in at-risk patients
IL-2R (CD25)	basiliximab	Transplant induction
IL-31	nemolizumab	Prurigo nodularis, atopic dermatitis pruritus

Cytokine release syndrome (CAR-T, bispecifics, alemtuzumab) - IL-6-driven; graded by fever/hypotension/hypoxia and treated with tocilizumab +/- steroid
Haemophagocytic lymphohistiocytosis / macrophage activation syndrome - IFN-gamma and IL-1/IL-18 driven; very high ferritin, treated with steroid, anakinra, emapalumab (anti-IFN-gamma)
Every cytokine blocker carries an infection risk that mirrors its physiology: anti-TNF -> TB and granulomatous infection; anti-IL-17 -> candida; anti-IL-6 -> masked sepsis; anti-IL-5 -> minimal, because eosinophils are largely dispensable

Correlations

T-helper subset pathways in autoimmune disease
Autoinflammatory syndromes and the inflammasome
Biologic therapy mechanisms in rheumatoid arthritis
Asthma phenotypes and biologic selection
Psoriasis, psoriatic arthritis and IBD
CAR-T therapy and cytokine release syndrome
Acute phase response, CRP and ferritin

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