This document summarizes various cytokine mediators and their functions. It discusses how cytokines are produced by different cell types and mediate effects through autocrine, paracrine and endocrine signaling. Specific cytokines discussed include interleukins (IL), interferons, tumor necrosis factor (TNF), and colony stimulating factors (CSFs). The roles of various cytokines in innate immunity, lymphocyte differentiation, and inflammation are described. Clinical uses of certain cytokines like IL-2, IL-11, anti-TNF antibodies, and GM-CSF are also mentioned.

1. Dr.Prashanth Sangu
Resident
Dept. of General Surgery

2.  DEFINITION: Peptide mediators or
intercellular messengers that regulate
immunological, inflammatory and reparative
host responses.
 Highly potent
 Includes
Interleukins
Interferons
Tumor necrosis factor
Colony stimulating factor
Others

3.  Produced by several different cell types.
eg;IL-1(leukocytes, endothelial cells, fibroblasts).
 Pleiotropic
 Redundancy
 Induce effects by-autocrine,
paracrine and
endocrine.
 Mediate actions by binding to high affinity
receptors on target cells.

4.  Innate immunity:IL-1,IL-6,TNF,type-1
Interferon.
 Regulate differentiation of lymphocytes:
IL-2:T cells
IL-4:TH-2 and B-cells
IL-12:TH-1
IL-15:NK cells.
 Activate inflammatory cells:IFN-gamma,IL-5,
TNF
 Stimulate haematopoiesis: CSFs.
 Affect leucocyte movement: chemokines.

9.  IL-1: LAF, BAF
 Stimulated by antigens, toxins {LPS from gram-
negative bacteria), lipoteichoic acid (from gram
positive bacteria), and zymosan (from yeast)},
physical injury, inflammatory processes.
 Inhibited by corticosteroids, cyclosporin A,
prostaglandins.
 Induce synthesis of endothelial adhesion
molecules and chemical mediators like
cytokines, chemokines, growth factors,
eicosanoids, nitric oxide.

11.  IL-2:T cell growth factor.
 Produced by activated T cells.
 Major activator of T and B cells.
 Converts some of null cells(LGL) into
lymphokine activated killer cells which can
destroy NK resistant tumor cells.
 USES: chronic granulomatous diseases.
 IL-3: growth factor for bone marrow stem cells.
 Also known as multi colony stimulating factor
(multi CSF).

12.  IL-4:B cell growth factor-1.
 Also acts as growth factor for mast cells, T cells.
 Augments Ig E synthesis.,
 IL-5:B cell growth factor-2.
 Induces maturation of eosinophils.
 IL-6: produced by stimulated T and B cells,
macrophages and fibroblasts.
 induction of fever, promotion of B cell maturation
and differentiation, differentiation of nervecells,
stimulation of the hypothalamicpituitary-adrenal
axis, and induction of the synthesis of acute-
phase proteins (e.g., C-reactive protein) by
hepatocytes.

13.  Circulating concentrations of IL-6 increase
dramatically after tissue injury.
 IL-11: is a hematopoietic growth factor with
particular activity as a stimulator of
megakaryocytopoiesis and thrombopoiesis.
 USES: Recombinant IL-11-mild von Willebrand
disease

14.  IL-12:Defective production of IL-12 by
peripheral blood mononuclear cells after
stimulation with IFN-γ and LPS is associated
with an increased risk for the development of
postoperative sepsis.
 IL-12 has also been implicated in the
pathogenesis of IBD.
 Treatment of patients with refractory IBD with
thalidomide, a potent anti-inflammatory agent,
decreases the production of TNF and IL-12 by
mononuclear cells isolated from the lamina
propria of gut mucosal biopsy samples and
decreases disease activity

15.  IL-18:induce production of IFN-γ by T cells and
NK cells.
 induces the production of CC and CXC
chemokines from human mononuclear cells
and activates neutrophils, an effect that may
contribute to organ injury and dysfunction in
conditions such as sepsis and ARDS.

16.  IL-4, IL-10, and IL-13 can be regarded as
inhibitory, anti-inflammatory, or counter
regulatory cytokines.
 IL-4 has many biologic actions that promote the
expression of the Th2 phenotype, characterized by
down regulation of proinflammatory and cell-
mediated immune responses and up regulation of
humoral (B cell–mediated)immune responses.
 IL-4 inhibits the production of TNF, IL-1, IL-8, and
PGE2 by stimulated monocytes or macrophages
and down regulates endothelial cell activation
induced by TNF.

17.  IL-10 inhibits the production of numerous
proinflammatory cytokines, including IL-1, TNF,
IL-6, IL-8, IL-12, and GM-CSF, by monocytes and
macrophages; on the other hand, it increases
synthesis of the counter regulatory cytokine IL-
1RA by activated monocytes.
 down regulates the proliferation and secretion of
IFN-γ and IL-2 by activated Th1 cells, primarily by
inhibiting the production of IL-12 by macrophages
 Production of IL-10 by peripheral blood
mononuclear cell and CD4+ T cells is increased in
trauma patients, and sepsis

18.  Additional anti-inflammatory properties of
IL-13 include inhibition of induction of the
enzyme COX-2, required for the production of
prostaglandins, and induction of an enzyme,
15-lipoxygenase, that catalyzes the formation of
a lipid mediator (lipoxin A4) with anti-
inflammatory properties.

19.  Species specific
 By producing translation inhibiting
protein(TIP)
protein kinase
oligonucleotide synthetase
RNAse
 Inactivated by proteolytic enzymes
 Resist heat 56-60C for 30-60min.,and stable
over Ph range of 2-10.
 Poorly antigenic

20.  TYPES:
Alpha: leucocytes
Beta: fibroblasts
Gamma: T-lymphocytes.
immunomodulatory, anti proliferative.
 Biological effects:
Anti viral
Anti bacterial
Immunoregulatory
Inhibits cell growth and proliferation

21.  USES:
 IFN-alpha: Hairy cell leukemia
CML, Malignant melanoma
kaposi sarcoma, RCC, carcinoid
Hepatitis B and C infections
 IFN beta: Multiple sclerosis(relapsing type)
 IFN gamma: Chronic granulomatous diseases
 Recombinant IFN-γ has been shown to reduce
the frequency of infections markedly in
patients with chronic granulomatous disease.
 Local application of high doses-URTI, genital
warts and herpetic keratitis.

22.  Serum factor found to induce haemorrhagic
necrosis in certain tumors.
 TYPES: TNF-αlpha(cachectin)
TNF-beta Lymphotoxin-α (LT-α)
 Other members of the TNF family include Fas
ligand (FasL), receptor activator of NF-κB ligand
(RANKL), CD40 ligand (CD40L) and TNF-related
apoptosis inducing ligand (TRAIL).
 TNF, IL-1, and IL-6 (as well as some other
proinflammatory cytokines) can activate the
extrinsic pathway of coagulation, in part by
promoting expression of tissue factor (TF), on
endothelial cells and monocytes.

23.  Anti TNF α MONOCLONAL ANTIBODIES.
 ADALIMUMAB: rheumatoid arthritis
 ETANERCEPT: Rheumatoid arthritis
Psoriatic arthritis
juvenile RA
 INFLIXIMAB: Crohn’s disease
Ulcerative colitis
Ankylosing spondylitis
Psoriatic arthritis
 IL-1 receptor antagonist - ANAKINRA

24.  C-X-C(alpha-chemokines):
acts on Neutrophils.
IL-8.
Inducers: microbial products,IL-1,TNF.
 C-C(beta-chemokines):
MCP-1(monocyte chemo attractant protein)
Eotaxin
MIP-1alpha(macrophage inflammatory protein)
RANTES
 C(gamma- chemokines): lymphotacin
 CX3C: fractalkine

25.  GM-CSF is a hematopoietic growth factor and
proinflammatory cytokine produced by multiple
cell types, including bronchial epithelial cells,
monocytes, and endothelial cells.
 As a growth factor, GM-CSF promotes an increase
in the number of circulating polymorphonuclear
nuclear cells (PMNs).
 Crohn’s disease may result, at least in part, from
impaired innate immunity (e.g., caused by a
mutation in the NOD2 gene), recombinant GM-
CSF might be a therapeutic option for this
condition.

26.  TGF-beta: effects includes modulation of cell
growth, inflammation, matrix synthesis, and
apoptosis.
 Macrophage migration inhibitory factor (MIF):
up regulates the expression of TLR4 on
macrophages, thereby amplifying the response
of the innate immune system to LPS.
 Leukemia inhibitory factor(LIF):eosinophil
chemotaxis.

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