Cytokines and Chemokines

Slide 1 · Cytokines and Chemokines

Inflammatory signaling, leukocyte recruitment, and systemic responses

Cytokine signals

Leukocyte movement

Systemic responses

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Learning outcomes

Identify principal cytokine sources and their major inflammatory actions.

Explain TNF- and IL-1–driven endothelial and leukocyte activation.

Relate cytokine effects to fever, acute-phase responses, and cachexia.

Distinguish chemokine families, receptors, and tissue-specific functions.

Slide 3 · Inflammation uses soluble mediators

Injury or microbial stimulus

Local danger signals initiate inflammation

Sentinel-cell response

Macrophages and dendritic cells release mediators

Target-cell activation

Endothelium and leukocytes change behavior

Tissue response

Recruitment, defense, and systemic manifestations

Cytokines coordinate cells; Chemokines help direct leukocyte movement.

Slide 4 · Cytokines: Functional definition

Protein mediators made by many cell types.

Regulate and mediate immune and inflammatory reactions.

Important producers include activated lymphocytes, macrophages, and dendritic cells.

Epithelial, endothelial, and connective tissue cells can also produce them.

Slide 5 · Immune cells and tissue cells both signal

Immune-cell sources

Activated T lymphocytes

Macrophages and dendritic cells

Mast cells; Selected cytokines

Resident-tissue sources

Endothelial and epithelial cells

Connective tissue cells

Site of injury becomes an active signaling compartment

Signaling is not restricted to circulating leukocytes.

Slide 6 · Scope: Inflammatory cytokines versus growth factors

Here, the principal focus is cytokines participating in inflammation.

Growth factors acting on epithelial and mesenchymal cells are conventionally considered separately.

Individual mediators can act on multiple cell types and have overlapping effects.

These slides emphasize tissue responses rather than a full catalogue of immune signaling.

Slide 7 · Major cytokines in acute inflammation

Mediator

Main source(s)

Characteristic role

TNF

Macrophages, DCs, mast cells, T cells

Endothelial activation; systemic effects

IL-1

Macrophages, DCs, epithelia

TNF-like actions; prominent fever role

IL-6

Macrophages, other cells

Acute-phase and systemic responses

IL-17

T lymphocytes

Neutrophil and monocyte recruitment

DC = dendritic cell. These mediators have distinct emphases but overlapping actions.

Slide 8 · Cytokines highlighted in chronic inflammation

Mediator

Principal source(s)

Key action

IL-12

Dendritic cells, macrophages

Increases interferon-γ production

IFN-γ

T and NK lymphocytes

Activates macrophage microbicidal responses

IL-17

T lymphocytes

Promotes neutrophil / monocyte recruitment

Acute/chronic categories overlap; The classification is functional, not absolute.

Slide 9 · Inflammatory signals form an interacting network

Activated innate cells

TNF

Endothelial activation

IL-1

Local and systemic effects

IL-6

Acute-phase response

These mediators have distinct emphases but substantial functional overlap.

Slide 10 · Acute and chronic cytokines overlap

Cytokines listed under acute inflammation can also act in chronic disease.

Chronic inflammation includes persistent leukocyte activation and additional lymphocyte-derived signals.

IL-12, IFN-γ, and IL-17 are prominent mediators in chronic inflammation.

Avoid treating acute and chronic cytokine lists as mutually exclusive.

Slide 11 · TNF is a central inflammatory amplifier

Tumor necrosis factor

Endothelium

Adhesion molecules and cytokines

Leukocytes

Enhanced responses to stimulation

Organ systems

Fever and metabolic consequences

The same mediator can have local protective and systemic pathological effects.

Slide 12 · Principal cellular sources of TNF

Activated macrophages and dendritic cells are major sources.

T lymphocytes and mast cells can also produce TNF.

The cellular source varies with the initiating stimulus and tissue microenvironment.

TNF can act on endothelial cells as well as recruited inflammatory cells.

Slide 13 · Diverse stimuli trigger TNF and IL-1

Biological stimuli

Microbial products

Dead or injured cells

Immune complexes

Other inflammatory stimuli

Foreign bodies

Physical injury

Other local triggers of inflammation

Cytokine release links danger recognition with an organized inflammatory response.

Slide 14 · Microbial sensing induces TNF

Microbial products

Recognized by TLRs and other sensors

Intracellular signals

Induce inflammatory gene expression

TNF production

Produced by stimulated sentinel cells

Tissue effects

Endothelial activation and leukocyte recruitment

TLR = Toll-like receptor; This is a simplified causal sequence.

Slide 15 · IL-1 shares stimuli but has an extra control step

Macrophages and dendritic cells are major sources of IL-1.

Some epithelial cells also produce IL-1.

Signals that induce TNF also stimulate IL-1 synthesis.

Generation of biologically active IL-1 depends on inflammasome activity.

Slide 16 · IL-1 requires synthesis and maturation

Inflammatory stimulus

Microbial sensing / cell damage signals

IL-1 synthesis

Production of the cytokine precursor

Inflammasome-dependent activation

Processing to biologically active IL-1

Effector response

Leukocyte recruitment and systemic effects

IL-1 protein synthesis and inflammasome-dependent activation are distinct steps.

Slide 17 · TNF and IL-1: Overlap and emphasis

Feature

TNF

IL-1

Main source

Macrophages / DCs; T cells and mast cells

Macrophages / DCs; some epithelia

Endothelial effect

Activation, adhesion molecules

Similar endothelial activation

Distinct emphasis

Cachexia / metabolic effects

Stronger role in fever

Upstream control

Microbial sensor signals

Inflammasome-dependent maturation

Overlap is substantial; “distinct emphasis” is not exclusivity.

Slide 18 · TNF and IL-1 initiate endothelial activation

TNF / IL-1

Signals released near inflammatory focus

Endothelial cells

Increase adhesion molecule expression

Leukocytes

Attach more effectively to vessel wall

Inflamed tissue

Increased extravasation into injured site

Endothelial activation is a prerequisite for efficient leukocyte recruitment.

Slide 19 · Endothelial activation changes the vessel wall

Up-regulates E-selectin and P-selectin.

Increases endothelial ligands for leukocyte integrins.

Stimulates additional inflammatory mediators and growth factors.

Increases the procoagulant activity of the endothelium.

Slide 20 · Selectins and integrin ligands are complementary

Selectins

E-selectin and P-selectin increase after activation.

Support early interactions between leukocytes and vessel wall.

Integrin ligands

Endothelial ligands support more stable leukocyte attachment.

Effective binding is enhanced by chemokine signaling to leukocytes.

Vessel-wall induction and leukocyte integrin activation cooperate.

Slide 21 · Leukocyte entry requires sequential signals

Activated endothelium

Adhesion molecules are displayed

Chemokines

Increase leukocyte integrin affinity

Firm leukocyte attachment

Stable interaction with endothelium

Migration

Leukocytes cross vessels and follow tissue signals

The steps represent distinct, coordinated components of recruitment.

Slide 22 · Activated endothelium becomes a signaling hub

TNF / IL-1 signal

Chemokines

Recruitment guidance

Cytokines

Amplify inflammatory communication

Eicosanoids

Additional inflammatory responses

The activated vascular wall is a source of mediators, not merely a passive barrier.

Slide 23 · Endothelial procoagulant changes

TNF and IL-1 can increase endothelial procoagulant activity.

This links inflammation to shifts in vascular hemostatic behavior.

When systemic responses become excessive, thrombosis may contribute to pathology.

Coagulation effects are one component of a wider cytokine response.

Slide 24 · TNF augments neutrophil responsiveness

TNF enhances neutrophil responses to other inflammatory signals.

Bacterial endotoxin is an example of a cooperating stimulus.

Augmented activation supports antimicrobial host defense.

In excessive inflammation, the same responses can contribute to tissue injury.

Slide 25 · TNF enhances macrophage microbicidal activity

TNF exposure

Macrophage activation

Induced nitric oxide

Part of increased microbicidal capacity

Microbial killing

More effective response to intracellular pathogens

Induction of nitric oxide (NO) contributes to macrophage microbicidal activity.

Slide 26 · IL-1 activates fibroblasts

IL-1 can stimulate fibroblasts to produce collagen.

The effect links an inflammatory mediator to mesenchymal cell responses.

This provides a mechanistic connection between persistent inflammation and matrix deposition.

The lecture scope is cytokine signaling, not a complete account of scar formation.

Slide 27 · IL-1 acts on mesenchymal and immune cells

Mesenchymal responses

Fibroblast collagen synthesis

Proliferation of synovial and other mesenchymal cells

Immune-cell responses

Stimulation of Th17 responses

Subsequent enhancement of inflammatory recruitment

One cytokine can influence both tissue remodeling and leukocyte responses.

Slide 28 · IL-1 can amplify Th17-associated inflammation

IL-1 signal

Favors Th17 responses

T-cell IL-17

Inflammatory cytokine release

Recruitment

Neutrophils and monocytes enter tissues

Local inflammation

Amplified cellular infiltrate

This is an explanatory cytokine sequence, not a complete model of T-cell differentiation.

Slide 29 · Local actions of TNF and IL-1

Target

Effect

Inflammatory consequence

Endothelium

Adhesion molecules and ligands

Leukocyte entry

Neutrophils / macrophages

Enhanced activation

Microbicidal defense

Fibroblasts

Collagen synthesis (IL-1)

Matrix production

Synovial cells

Proliferation (IL-1)

Mesenchymal expansion

Different target cells translate the same extracellular signal into distinct outcomes.

Slide 30 · Cytokines have local and systemic effects

TNF · IL-1 · IL-6

Local

Adhesion, leukocyte activation

Systemic protective

Fever, leukocytosis, acute-phase proteins

Systemic harmful

Metabolic and circulatory pathology

Magnitude, duration, and distribution influence whether the response protects or injures.

Slide 31 · Fever is a cytokine-driven systemic response

IL-1 and TNF participate in the febrile response.

IL-1 has a particularly prominent role in fever.

Cytokine-associated prostaglandin E₂ contributes to fever.

Fever is one of several coordinated systemic responses to infection or injury.

Slide 32 · Cytokines stimulate the acute-phase response

Infection or tissue injury

Macrophage / stromal cytokine release

IL-6 prominence

Signal to hepatic acute-phase response

Liver

Synthesis of acute-phase proteins

Circulation

CRP, fibrinogen, serum amyloid A increase

IL-6 is a major driver of hepatic acute-phase protein synthesis.

Slide 33 · Acute-phase proteins are downstream readouts

C-reactive protein (CRP) is an acute-phase protein.

Fibrinogen and serum amyloid A are additional examples.

Their synthesis reflects cytokine-driven hepatic responses.

They are systemic correlates of inflammation, not the initiating cytokines.

Slide 34 · Inflammation can increase circulating leukocytes

Inflammatory cytokines

Signal beyond the local tissue

Bone marrow response

Increased leukocyte output

Leukocytosis

Greater numbers of circulating inflammatory cells

Leukocytosis increases the circulating pool of host-defense leukocytes.

Slide 35 · Systemic responses: Protective and pathological

Protective responses

Fever

Leukocytosis

Increased acute-phase proteins

Potentially pathological responses

Circulatory dysfunction

Abnormal coagulation / thrombosis

Metabolic derangement and wasting

Physiological defense becomes harmful when responses are excessive or sustained.

Slide 36 · TNF participates in systemic metabolic regulation

TNF promotes mobilization of lipids and proteins.

TNF suppresses appetite.

Sustained production promotes negative nutritional and energy balance.

These actions can contribute to cachexia in chronic disease.

Slide 37 · Persistent TNF can contribute to cachexia

Persistent inflammation

Sustained TNF production

Metabolic effects

Lipid/protein mobilization

Appetite suppression

Reduced nutritional intake

Cachexia

Pathological weight loss and anorexia

Examples include some chronic infections and neoplastic diseases.

Slide 38 · Cachexia is not merely a local inflammatory sign

Cachexia includes anorexia and pathological weight loss.

It is associated with persistent inflammatory cytokine activity.

TNF is one important contributor, not a complete single-factor explanation.

Understanding systemic cytokine action explains why localized disease can cause generalized wasting.

Slide 39 · Systemic cytokine effects span multiple organs

Circulating mediators

Brain

Fever; Appetite modulation

Liver and marrow

Acute phase; Leukocytosis

Vessels and tissues

Coagulation and metabolic responses

Circulating inflammatory cytokines affect organs distant from the original lesion.

Slide 40 · TNF blockade illustrates clinical relevance

TNF antagonists are effective treatments for several chronic inflammatory diseases.

Examples include rheumatoid arthritis and psoriasis.

Certain forms of inflammatory bowel disease are additional examples.

Treatment benefit demonstrates the importance of TNF in disease pathogenesis.

Slide 41 · TNF blockade can impair intracellular defense

TNF antagonist

Reduced TNF signaling

Macrophage response

Reduced ability to kill intracellular microbes

Clinical consequence

Greater susceptibility to mycobacterial infection

This risk follows directly from the host-defense function of TNF.

Slide 42 · TNF and IL-1 inhibition are not interchangeable

TNF blockade

Notable efficacy in several chronic inflammatory diseases

Important intracellular infection risk

IL-1 blockade

Some overlapping biological targets

Not uniformly as effective for the diseases discussed

Reasons for the difference in effectiveness remain incompletely understood.

Slide 43 · Sepsis is not a single-cytokine disease

Inflammatory systemic responses can involve several cytokines simultaneously.

Blocking either TNF or IL-1 alone has not improved sepsis outcomes in the studies discussed.

Redundancy and mediator interactions may limit single-target interventions.

Therapeutic inference must not be confused with a complete contemporary treatment guideline.

Slide 44 · Chemokines specialize in cellular navigation

Small proteins with a principal role as leukocyte chemoattractants.

Recruit specific leukocyte populations in inflammation.

Also organize cell distribution within normal tissues.

They are typically small proteins of approximately 8–10 kDa.

Slide 45 · Chemokines have two biological contexts

Inflammatory chemokines

Induced by microbes and inflammatory signals

Promote attachment and migration to sites of injury

Homeostatic chemokines

Produced constitutively in tissues

Maintain localization of cells within tissue compartments

Chemotaxis is essential in both defense and normal tissue organization.

Slide 46 · Four chemokine families: Cysteine arrangement

Family

Conserved N-terminal cysteines

Example

CXC

C–X–C: one residue between

CXCL8 (IL-8)

CC

C–C: adjacent pair

CCL2 / CCL11 / CCL3

C

Two of four conserved Cys absent

XCL1 (lymphotactin)

CX3C

C–X₃–C: three intervening residues

CX3CL1 (fractalkine)

Classification refers to spacing of conserved cysteine residues.

Slide 47 · A subset of CXC chemokines recruits neutrophils

Inflammatory stimulus

Microbes or TNF / IL-1 signals

CXCL8 release

Activated macrophages and endothelial cells

Neutrophils

Activation and directed migration to tissue

A subset of CXC chemokines is especially active on neutrophils.

Slide 48 · CXCL8 is the former interleukin-8

IL-8 is now designated CXCL8.

Made by activated macrophages, endothelial cells, and additional cell types.

Promotes neutrophil activation and chemotaxis.

Has comparatively limited effects on monocytes and eosinophils.

Slide 49 · CXCL8 production is itself cytokine regulated

Microbial products

Direct inflammatory induction

TNF

Induces local chemokine production

IL-1

Also induces chemokine production

CXCL8 secretion

Neutrophil activation and chemotaxis

TNF and IL-1 can indirectly recruit neutrophils by inducing chemokines.

Slide 50 · CC chemokines target broader leukocyte sets

Conserved first two cysteines are adjacent.

Common targets: Monocytes, eosinophils, basophils, and lymphocytes.

In general, CC chemokines are less potent than some CXC members for neutrophils.

Functional overlap exists among the many CC family members.

Slide 51 · Illustrative CC chemokines

Chemokine

Alternative name

Source-supported association

CCL2

MCP-1

Monocyte chemoattractant

CCL11

Eotaxin

Relatively selective eosinophil recruitment

CCL3

MIP-1α

CC-family leukocyte chemoattraction

Examples are not an exhaustive receptor–ligand catalogue.

Slide 52 · CCL2 illustrates monocyte recruitment

CCL2 is also called monocyte chemoattractant protein-1 (MCP-1).

It belongs to the CC family of chemokines.

Its name reflects an important monocyte-directed chemoattractant role.

This differs from neutrophil-dominant CXCL8 signaling.

Slide 53 · CCL11 illustrates selective recruitment

CCL11 is commonly known as eotaxin.

It shows relatively selective eosinophil recruitment.

This shows that chemokines can confer leukocyte-subset preference.

Subset preference helps explain differing cellular compositions of infiltrates.

Slide 54 · CCL3 is a further CC-family example

CCL3 was historically called macrophage inflammatory protein-1α.

It is listed alongside CCL2 and CCL11 in the CC group.

Its inclusion underscores the diversity of leukocyte-active chemokines.

Family membership alone does not specify an exclusive single target cell.

Slide 55 · Rare structural families add specificity

C family

Example: XCL1 / lymphotactin

Missing first and third of four conserved cysteines

Relatively specific for lymphocytes

CX3C family

Example: CX3CL1 / fractalkine

Three residues separate first two conserved cysteines

Can support adhesion or chemoattraction

These structural families are not interchangeable with the CXC and CC families.

Slide 56 · Fractalkine has two biologically distinct forms

Cell-surface CX3CL1

Induced on endothelium by cytokines

Membrane-bound action

Strong monocyte and T-cell adhesion

Proteolytic cleavage

Soluble CX3CL1 is released

Soluble action

Chemoattraction of monocytes and T cells

One chemokine therefore supports both attachment and migration.

Slide 57 · Chemokine receptors are seven-pass GPCRs

Chemokine ligand

Binds a matching cell-surface receptor

7-transmembrane GPCR

G protein–coupled signal transduction

Leukocyte response

Increased integrin affinity and directed migration

GPCR = G protein–coupled receptor.

Slide 58 · Leukocytes express multiple chemokine receptors

Most leukocytes display more than one receptor type.

Consequently, a cell can respond to more than one chemokine signal.

Multiple ligand–receptor interactions permit overlapping recruitment programs.

This complexity helps explain difficulty of single-receptor inhibition.

Slide 59 · Endothelium presents chemokines to passing cells

Local cytokines / injury

Chemokines released

Endothelial proteoglycans

Chemokines retained at high surface concentration

Passing leukocyte

Encounters displayed chemokine

Integrin activation

Increased adhesion affinity

Extracellular matrix proteoglycans can also bind chemokines locally.

Slide 60 · Chemokines activate leukocyte integrin binding

Leukocyte near endothelium

Integrins present on cell surface

Chemokine receptor signal

Integrin affinity rises

Endothelial integrin ligand

Stable adhesive interaction

Transmigration

Leukocyte reaches inflamed tissue

Chemokines change leukocyte adhesive behavior rather than merely increasing cell movement.

Slide 61 · Tissue gradients direct leukocyte chemotaxis

Chemokine at inflamed focus

Local production in response to injury

Matrix-associated distribution

Spatially localized chemokine cue

Recruited leukocyte

Directional movement toward the focus

Directed tissue chemotaxis is a principal inflammatory chemokine function.

Slide 62 · Inflammatory versus homeostatic chemokines

Property

Inflammatory

Homeostatic

Production

Induced by damage / microbes

Constitutive

Principal task

Recruit leukocytes to tissue lesion

Maintain normal tissue organization

Important outcome

Inflammatory infiltrate

Cell positioning in lymphoid tissues

The distinction refers to typical biological roles, not separate protein chemistry.

Slide 63 · Homeostatic chemokines organize lymphoid tissue

Constitutively produced chemokines influence cell localization.

They help segregate T and B lymphocytes into discrete regions.

The spleen and lymph nodes show this organized lymphocyte distribution.

Normal architecture therefore depends in part on chemokine-directed positioning.

Slide 64 · Two contexts, one principle: Directed movement

Chemokine signal

Infection

Recruit effector leukocytes

Vessel wall

Increase integrin affinity

Lymphoid organ

Position lymphocyte subsets

Chemokines convey positional information in both inflammatory and physiological settings.

Slide 65 · Certain chemokine receptors are HIV coreceptors

CXCR4 and CCR5 can act as HIV coreceptors.

They participate in viral binding and entry into susceptible cells.

Their role in infection is distinct from their usual chemokine-signaling functions.

This illustrates a noninflammatory consequence of chemokine receptor expression.

Slide 66 · Chemokine-targeted therapy is challenging

Chemokine-mediated inflammation is well established experimentally.

Most leukocytes express multiple receptor types.

Many chemokine ligands display overlapping leukocyte actions.

Effective therapeutic chemokine antagonism has proven challenging.

Slide 67 · IL-6 is prominent in the acute-phase response

Macrophages and other cells

IL-6 is released

Circulating IL-6

Promotes systemic responses

Liver

Acute-phase protein production

IL-6 participates in local inflammation in addition to systemic reactions.

Slide 68 · IL-17 promotes myeloid leukocyte recruitment

Activated T lymphocytes

Major IL-17 source

IL-17 release

Promotes inflammatory recruitment

Inflamed tissue

Neutrophils and monocytes accumulate

IL-17 is relevant to acute as well as chronic inflammatory responses.

Slide 69 · Targeting IL-6 and IL-17 has clinical effects

IL-6 receptor inhibition

Example: Juvenile arthritis

Interferes with an important inflammatory cytokine pathway

IL-17 inhibition

Example: Psoriasis

Reduces signaling associated with myeloid recruitment

Examples illustrate mechanism-based therapy; They are not comprehensive prescribing guidance.

Slide 70 · One-page cytokine functional map

Mediator

Primary role emphasized

Cells / systems affected

TNF

Endothelial activation; cachexia

Vessels, leukocytes, metabolism

IL-1

Endothelial activation; fever

Vessels, fibroblasts, systemic

IL-6

Acute-phase response

Liver and systemic sites

IL-17

Recruitment of myeloid cells

Neutrophils and monocytes

Chemokines

Adhesion and chemotaxis

Specific recruited leukocytes

Functional emphasis from Chapter 3; Actions are not mutually exclusive.

Slide 71 · Application: Neutrophil-rich inflammation

Clinical reasoning prompt

An infected tissue becomes enriched in neutrophils. Nearby macrophages and endothelial cells are producing inflammatory mediators.

Which named chemokine best illustrates directed neutrophil recruitment?

Mechanistic explanation

CXCL8 (IL-8). It is induced by microbes and TNF / IL-1, and activates and attracts neutrophils.

Slide 72 · Application: Cytokine inhibition and infection

Clinical reasoning prompt

A patient receiving a TNF antagonist develops concern for an intracellular infection.

Which normal TNF function explains this susceptibility?

Mechanistic explanation

TNF helps macrophages kill intracellular microbes, in part through NO-associated microbicidal activation.

Slide 73 · Application: Endothelial activation

Clinical reasoning prompt

Inflamed endothelium displays more adhesion molecules while passing leukocytes respond to nearby chemokines.

Identify the complementary roles of TNF / IL-1 and chemokines.

Mechanistic explanation

TNF / IL-1 induce endothelial adhesion machinery; Chemokines increase leukocyte integrin affinity and direct tissue migration.

Slide 74 · Synthesis: Five mechanistic relationships

TNF and IL-1 convert danger signals into endothelial activation.

IL-1 activity requires inflammasome-dependent maturation.

IL-6 is a major mediator of the hepatic acute-phase response.

Chemokines connect leukocyte adhesion to directed tissue migration.

Excess or persistent cytokine activity can produce systemic pathology.

Slide 75 · Primary reference

Robbins, Cotran & Kumar: Pathologic Basis of Disease. 11th edition (2026).

Chapter 3: Inflammation and Repair.

Section: Cytokines and Chemokines; Table 3.7 and Figure 3.10.

Figure- and table-derived concepts have been redrawn as original editable teaching schematics.