Cytokines
An organ with no anatomy
Every other organ you have studied this year has a shape. The liver sits under the diaphragm; the heart has four chambers you can dissect. The immune system has none of that. Its hundreds of millions of cells are scattered through every tissue in the body, and they still have to act together — the right cell has to be told to divide, the right cell has to be summoned to the right place, and the whole response has to be switched off again when it is done.
There are only two ways for one cell to instruct another: touch it, or send it something. Touching is done by membrane molecules — CD, CAM, MHC, TCR, BCR, which are the next several units. Sending is done by cytokines, and that is this one. Take the cytokines away and you do not get a weakened immune system; you get a collection of individually competent cells that cannot coordinate at all.
The comparison the lecture draws is with the endocrine system, and it is worth holding because it makes the differences memorable. Hormones and cytokines are both secreted chemical messages that act through high-affinity receptors. But a hormone usually acts at a distance, carried in blood to a distant organ, whereas a cytokine usually acts locally, on the cell next door or on itself. And unlike growth factors, which are produced constitutively, cytokine production is tightly regulated — made only when needed, and stopped quickly.
- What are the two ways immune cells communicate? → Membrane contact molecules, and soluble cytokines
- Name the main membrane molecules. → CD, CAM, MHC, TCR, BCR
- How do cytokines differ from hormones? → Cytokines act locally; hormones usually act at a distance
- How do cytokines differ from growth factors? → Growth factors are made constitutively; cytokine production is carefully regulated
The definition ★★★
Cytokine (CK) has been set as a Section I definition in both papers we hold — one of only three terms to appear twice. Learn this one properly; it is close to a guaranteed three marks.
Any of numerous secreted, low-molecular-weight proteins that regulate the intensity and duration of the immune response by exerting a variety of effects on lymphocytes and other immune cells that express the appropriate receptor.Section I, 2019 AND 2020
Notice what the definition does and does not say. It says low molecular weight and secreted. It says regulate intensity and duration — cytokines tune a response, they do not recognise anything. And the final clause is the one students drop: a cytokine acts only on cells expressing the appropriate receptor. That clause is where the selectivity lives, and it explains the answer to MCQ Q15 in §4.
Three older names you still meet
| Term | Means |
|---|---|
| Monokine | A cytokine produced by mononuclear phagocytes |
| Lymphokine | A cytokine produced by lymphocytes |
| Interleukin (IL) | Originally, a cytokine produced by leukocytes acting on other leukocytes |
These names are historical and slightly misleading — they classify by who made it, and it turned out that the same cytokine is often made by several unrelated cell types. IL-6, for example, comes from macrophages, endothelial cells and T cells alike. That is why the modern classification in §5 is by function and structure instead.
- Give the definition of a cytokine. → Secreted low-molecular-weight proteins that regulate the intensity and duration of the immune response, acting on cells that express the appropriate receptor
- What is a monokine? → A cytokine made by mononuclear phagocytes
- What is a lymphokine? → A cytokine made by lymphocytes
- Why are those older terms unsatisfactory? → The same cytokine is often made by several different cell types
How cytokines act ★★
Two general properties first, because they explain the pharmacology. Cytokine secretion is a brief, self-limited event: cytokines are not stored as preformed molecules, so a cell that needs one must transcribe and translate it, and once synthesised it is secreted immediately. And synthesis is promiscuous in both directions — different cell types make the same cytokine (IL-6 from macrophages, endothelium and T cells), and one cell type makes many different cytokines (a Th cell makes IL-2, IL-4, IL-5, IL-10, IFN-γ and more).
| Mode | Target | Example of the idea |
|---|---|---|
| Autocrine | The same cell that secreted it | A T cell making IL-2 and driving its own proliferation |
| Paracrine | A nearby cell | The commonest mode — this is why cytokines are described as acting locally |
| Endocrine | Distant cells, reached through the circulation | How a local infection produces systemic fever and acute-phase response |
Because cytokines are not stockpiled and are destroyed quickly, their effect is normally confined in both time and space — a burst, locally, then silence. Almost every serious cytokine-related illness is a failure of exactly that containment: the response stops being paracrine and becomes endocrine, and a local signal becomes a whole-body one. That is the cytokine storm in §9, and it is also why therapeutic cytokines are so difficult to dose — you are trying to reproduce a local burst with a systemic injection.
- Are cytokines stored ready-made? → No — synthesis is followed immediately by secretion
- Name the three modes of action. → Autocrine, paracrine, endocrine
- Which is the usual mode? → Paracrine — cytokines mainly act locally
- Give an example of one cytokine from several cell types. → IL-6, from macrophages, endothelial cells and T cells
The five attributes ★★★
This is the most examined idea in the unit, and it is examined by asking you which property cytokines lack. Learn the five that they have, and the absent one becomes obvious.
| Attribute | Meaning |
|---|---|
| Pleiotropism | One cytokine mediates diverse biological effects by acting on different target cells |
| Redundancy | Multiple cytokines mediate the same biological effect |
| Synergy | Two cytokines together produce an effect greater than expected from either alone |
| Antagonism | Two cytokines oppose each other's action |
| Cascade induction | One cytokine stimulates production of others, so a second or third cytokine actually mediates the first one's biological effect |
Draw it as arrows. Pleiotropism is one arrow fanning out — IL-4 acts on B cells, T cells and mast cells and does something different to each. Redundancy is many arrows converging — IL-2, IL-4 and IL-15 will all drive T-cell proliferation. Between them they guarantee that the cytokine network cannot be specific: no single message means one thing, and no single message is irreplaceable.
That has a real consequence. Redundancy is why knocking out one cytokine gene often produces a surprisingly mild phenotype, and why blocking a single cytokine therapeutically so often disappoints — something else covers for it.
Pleiotropism · Redundancy · Synergy · Antagonism · Cascade induction. If a question offers you a sixth option, it is the wrong answer — and the option the examiner actually uses is specificity.
- Name the five attributes of cytokines. → Pleiotropism, redundancy, synergy, antagonism, cascade induction
- Which property do cytokines NOT have? → Specificity — that belongs to TCR, BCR and antibody. This is MCQ Q15
- Define pleiotropism. → One cytokine has diverse effects on different target cells
- Define redundancy. → Several different cytokines produce the same effect
- Define cascade induction. → One cytokine induces others, which carry out the first one's effect
The six classes ★★
| Class | What it does | Members |
|---|---|---|
| Interleukin (IL) | Originally cytokines made by leukocytes acting on leukocytes | IL-1 to IL-39 |
| Interferon (IFN) | Interferes with viral infection and replication | Type I: IFN-α, IFN-β — from DCs and infected cells Type II: IFN-γ — from activated T cells and NK cells |
| Tumour necrosis factor (TNF) | Causes necrosis of tumour cells; promotes inflammation | TNF-α · TNF-β (lymphotoxin) |
| Colony-stimulating factor (CSF) | Stimulates formation of cell colonies in bone marrow culture | GM-CSF, M-CSF, G-CSF |
| Growth factor (GF) | Stimulates cell growth or proliferation | NGF, EGF, VEGF, FGF, PDGF |
| Chemokine | Chemotactic cytokines — stimulate leukocyte movement and regulate migration from blood into tissues | Classified by primary structure: CXC, CC, C, CX3C (C = cysteine, X = any amino acid) |
The interferon split is worth a moment because the naming is unhelpfully similar. Type I (IFN-α and IFN-β) is the antiviral interferon — made by infected cells and dendritic cells, and its job is literally to interfere with viral replication in neighbouring cells. Type II (IFN-γ) is made by activated T cells and NK cells and is mainly an immune-activating molecule — Janeway's calls it the principal macrophage-activating cytokine. Same word, different jobs: one blocks viruses, the other switches on macrophages.
The letters describe the spacing of the first two cysteines. CC — two cysteines adjacent. CXC — one amino acid between them. CX3C — three amino acids between. C — only one cysteine. You are being asked to read a structural fact out of the name, not memorise a list.
- Name the six classes of cytokine. → Interleukin · interferon · TNF · CSF · growth factor · chemokine
- Which interferons are type I, and from where? → IFN-α and IFN-β, from DCs and infected cells
- Which is type II, and from where? → IFN-γ, from activated T cells and NK cells
- What do chemokines do? → Stimulate leukocyte movement and regulate migration from blood into tissue
- What do the letters in CXC mean? → C = cysteine, X = any amino acid — the spacing of the first two cysteines
Th1 and Th2 — the profiles the exam turns on ★★★
The Th1/Th2 split does not appear in the Lecture 5 cytokines deck at all — not once. TMU teaches it in Lecture 7 (Immune Cells), slides 139–144, which is Unit 7. It is taught here because the two exam items that depend on it are cytokine questions, and because one of them is the single most dangerous item on the whole paper.
A naïve CD4⁺ helper T cell starts as Th0, secreting a broad spectrum of cytokines at low level. Depending on what it meets, it commits to one of two lineages — and the commitment is decided by cytokines, which is why this belongs in a cytokine unit. IL-12 and IFN-γ drive Th0 → Th1. IL-4 drives Th0 → Th2. Once committed, each lineage makes cytokines that reinforce itself and inhibit the other, so the choice becomes self-locking.
| Th1 | Th2 | |
|---|---|---|
| Cytokines produced | IL-2, IFN-γ, TNF — but not IL-4 | IL-4, IL-5, IL-6, IL-10, IL-13 — but not IL-2 or IFN-γ |
| Driven by | IL-12 and IFN-γ | IL-4 |
| Promotes | Cellular immunity | Humoral immunity |
| Acts on | Macrophages and phagocytes — intracellular killing; promotes NK function and CTL proliferation | B cells — activation, proliferation, differentiation and antibody production; eosinophil activation |
| Antibody class helped | IgG2a (little IgG1 or IgE) | IgG1 and IgE |
| Hypersensitivity | Type IV (delayed-type) | Type I (immediate) |
| Also involved in | Certain autoimmune diseases | Defence against parasites |
This is the strongest argument on the whole site against memorising the repeated paper. Every other true/false statement was identical across the two years. A student who learnt the 2019 answer key by heart, without understanding what Th1 and Th2 actually secrete, walks into 2020 and scores 11 out of 12 — and will never know why. Learn the two columns above and the question is trivial in either direction.
TMU Lecture 7, slide 139 says Th1 cells produce “IL-2, IFN-γ and TNF-α, but not IL-4”.
The circulated student review sheets say IFN-γ, IL-2 and TNF-β.
Janeway's 10e shows Th1 cells releasing “IFN-γ, TNF-α, and lymphotoxin (LT)” — and lymphotoxin-α is TNF-β.
So both are correct: Th1 cells make TNF-α and lymphotoxin/TNF-β. IFN-γ and IL-2 are beyond doubt. For the third blank, writing TNF is safest; if the form is demanded, use TNF-α, matching your department's own wording. Do not let a student review sheet talk you out of what your lecturer's slide says.
Look at the cytokines each one makes and where they point. Th1's IFN-γ suppresses Th2 development; Th2's IL-4 and IL-10 suppress Th1. So the immune system is not choosing between two settings on a dial — it is flipping a switch that then holds itself in position. That is exactly what you want when the two programmes are incompatible: you cannot simultaneously send macrophages to kill an intracellular organism and instruct B cells to make IgE against a worm. Committing hard to one is better than doing both badly.
It also explains a clinical pattern you meet later — in leprosy, the same organism produces mild tuberculoid disease in a Th1-dominant patient and severe lepromatous disease in a Th2-dominant one. Same bacterium; the outcome is decided by which switch the patient threw.
- Which cytokines does Th1 secrete? → IL-2, IFN-γ, TNF — and NOT IL-4
- Which does Th2 secrete? → IL-4, IL-5, IL-6, IL-10, IL-13 — and NOT IL-2 or IFN-γ
- Which cytokines drive Th0 to each lineage? → IL-12 and IFN-γ → Th1; IL-4 → Th2
- Which immunity does each promote? → Th1 cellular; Th2 humoral
- Which hypersensitivity does each mediate? → Th1 → type IV; Th2 → type I
- Which antibody classes does Th2 help? → IgG1 and IgE
- IL-4, IL-5, IL-10 belong to which subset? → Th2 — this is the True/False trap
Biological activities ★★
| Role | Cytokines involved |
|---|---|
| Mediate and regulate innate immunity — antibacterial | IL-1, TNF, IL-12 |
| Mediate and regulate innate immunity — antiviral | IFN-α, IFN-β (type I) |
| Mediate and regulate adaptive immunity | IL-2, IL-4, IL-5, IL-6, IFN-γ |
| Stimulate haematopoiesis | CSF, IL-7, EPO, IL-6, IL-11, TPO |
Notice how the grouping tracks the classes in §5. The antiviral row is type I interferon doing exactly what its name promised. The haematopoietic row is the colony-stimulating factors doing what their name promised. If you can recall the class names, you can reconstruct most of this table rather than memorising it.
- Which cytokines drive antibacterial innate immunity? → IL-1, TNF, IL-12
- Which drive antiviral innate immunity? → IFN-α and IFN-β
- Which regulate adaptive immunity? → IL-2, IL-4, IL-5, IL-6, IFN-γ
- Which stimulate haematopoiesis? → CSF, IL-7, EPO, IL-6, IL-11, TPO
Cytokine receptors
A cytokine does nothing unless the target cell carries its receptor — the clause at the end of the definition in §2. Every cytokine receptor is a transmembrane protein with three parts: an extracellular portion that binds the cytokine, a transmembrane region, and a cytoplasmic portion that starts the intracellular signalling.
- Type I cytokine receptors
- Type II cytokine receptors
- TNF receptor family
- Immunoglobulin superfamily receptors — the Ig fold again, as in Unit 3
- Chemokine receptor family
Some cytokine receptors detach from the cell membrane to form soluble receptors, which competitively antagonise the effects of the cytokine by binding it before it reaches a cell-bound receptor.
A soluble receptor is a decoy: it has the binding site but no cell attached, so anything it captures is neutralised. This is not just a curiosity — it is the design principle behind etanercept, a soluble TNF receptor fused to an Fc fragment, used in rheumatoid arthritis. The drug is a manufactured version of a regulatory mechanism you already have.
- Name the three structural parts of a cytokine receptor. → Extracellular binding portion, transmembrane region, cytoplasmic signalling portion
- Name the five receptor families. → Type I, type II, TNF receptor, Ig superfamily, chemokine receptor
- What does a soluble cytokine receptor do? → Competitively antagonises the cytokine by binding it in solution
Cytokine storm
The pathological secretion of extremely high levels of cytokines, induced by massive infection with particular pathogens. Typical features are increased capillary permeability with consequent loss of blood pressure and shock, sometimes leading to death.
Everything §3 said about containment is reversed here. Cytokine production stops being brief, local and self-limited; it becomes sustained, systemic and self-amplifying — cascade induction, from §4, running without a brake. The listed consequences are clotting, shock, renal failure, cell death, lung injury and immune paralysis, leading to inflammation, organ failure and further infection.
This is the same lesson as the superantigen in Unit 2, and it is one of the most important ideas in clinical immunology: a patient in a cytokine storm is being injured by their own immune system, not directly by the organism. It is why severe sepsis can progress after the bacteria have been killed, and why immunosuppressive treatment can be the right answer in a patient who is, on the face of it, overwhelmed by infection.
It is also why immune paralysis appears on the list of consequences — the storm exhausts the system it belongs to, leaving the patient vulnerable to the next organism.
- Define cytokine storm. → Pathological secretion of extremely high cytokine levels after massive infection
- What are the typical features? → Increased capillary permeability, loss of blood pressure, shock, sometimes death
- Which normal cytokine property has failed? → Brief, local, self-limited secretion — it becomes systemic and self-amplifying
- Why can immunosuppression help a severely infected patient? → Much of the injury is caused by the immune response itself
Revision layer
The exam map for this unit
| Section | Item | From |
|---|---|---|
| I. Definitions | Cytokine (CK) — set in BOTH years | §2 |
| III. MCQ Q15 | Specificity is NOT a cytokine property | §4 |
| II. Fill in blanks | Cytokines secreted by Th1 — set 2020 | §6 |
| IV. True/False Q3 | ⭐ The item that flips between years — Th1 (F) vs Th2 (T) | §6 |
The whole unit on one screen
| Question | Answer |
|---|---|
| Definition? | Secreted low-MW proteins regulating the intensity and duration of the immune response, acting on cells bearing the appropriate receptor |
| Three modes of action? | Autocrine · paracrine · endocrine |
| Five attributes? | Pleiotropism · redundancy · synergy · antagonism · cascade induction |
| The attribute they LACK? | Specificity |
| Six classes? | IL · IFN · TNF · CSF · GF · chemokine |
| Type I vs type II interferon? | I = IFN-α/β (antiviral, from DC and infected cells); II = IFN-γ (from activated T and NK) |
| Chemokine subfamilies? | CXC · CC · C · CX3C |
| Th1 cytokines? | IL-2, IFN-γ, TNF — not IL-4 |
| Th2 cytokines? | IL-4, IL-5, IL-6, IL-10, IL-13 — not IL-2 or IFN-γ |
| What drives each lineage? | IL-12 + IFN-γ → Th1; IL-4 → Th2 |
| Th1/Th2 and hypersensitivity? | Th1 → type IV; Th2 → type I |
| Receptor families? | Type I · type II · TNFR · Ig superfamily · chemokine receptor |
| Soluble cytokine receptor? | Detached receptor that competitively antagonises its cytokine |
| Cytokine storm? | Pathological massive cytokine release → capillary leak, hypotension, shock |
- Give the cytokine definition. → Secreted, low-molecular-weight proteins regulating the intensity and duration of the immune response via specific receptors
- Which property do cytokines lack, and who has it? → Specificity — TCR, BCR and antibody have it
- Name the five attributes. → Pleiotropism, redundancy, synergy, antagonism, cascade induction
- Th1 secretes? → IL-2, IFN-γ, TNF
- Th2 secretes? → IL-4, IL-5, IL-6, IL-10, IL-13
- IL-4, IL-5, IL-10 — Th1 or Th2? → Th2. Getting this right is the difference between 11/12 and 12/12
- Which cytokines are antiviral? → IFN-α and IFN-β
- What is a cytokine storm? → Pathological massive cytokine secretion causing capillary leak, shock and organ failure