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1. M.Prasad Naidu
MSc Medical Biochemistry,

2. Introduction
 Cytokines are peptides synthesized and released by white
blood cells and tissue macrophages that stimulate or
suppress the functional activity of lymphocytes, monocytes,
neutrophils, fibroblast cells, and endothelial cells.
 Cytokines are substances released by leukocytes and other
cells that control the development of the immune response.

3.  Often termed the hormones of the immune system, they
modulate the differentiation and division of hematopoietic
stem cells and activation of lymphocytes and phagocytes.
 Corticosteroids were among the earliest compounds found to
have immuno suppressive activity.

4.  The binding of the glucocorticoids to their receptors blocks
the synthesis or release of lymphokines and cytokines.
 This results in an inhibition of T-cell response to
stimulation, a redistribution of lymphocytes from the
vascular to the lymphatic system, and a decrease in the
number of circulating T-cells and B-cells.
 The cellular immune response is blunted, but almost no
immuno suppressive effect is seen in the humoral response
(antibody production).

5.  Cytokines are soluble proteins that interact with specific
cellular receptors that are involved in the regulation of the
growth and activation of immune cells and mediate normal
and pathologic inflammatory and immune responses.
 Cytokines are peptides used by cells for intercellular
communication and for controlling the inner environment of
the cells in which they operate.

6.  They are produced by cell types that have important roles in
the immune response, inflammation, hemopoiesis, healing,
and systemic response to injury.
 Many cytokines can be measured by bioassay and
immunoassay.

7. Clinical significance
Cytokines and the inflammatory process
 The immunoinflammatory system is a complex network of
cells and humoral elements that includes many cytokines.
 Typically, an immunoinflammatory response is triggered by
an antigen.

8.  The antigen is presented by specialized cells termed antigen-
presenting cells (APCs) that present the antigen through
either class I or II restriction of the major histocompatibility
complex (MHC).
 CD4 lymphocytes have two subtypes: Th1 and Th2.

10.  The transformation of CD4 lymphocytes into Th1 or Th2
subtypes is currently thought to be the central stage of the
immune response.
 Although unconfirmed, it is thought that Th0 lymphocytes
can polarize into Th1 or Th2 cells according to the cytokines
contained in the micro-environment in which the cells
reside.
 When CD4 lymphocytes are transformed into Th1 or Th2
subtypes, they produce a characteristic cytokine profile.

13.  The figure represents a general scheme of the development
of human CD4 Th1 cells.
 The figure summarizes the Th2 polarization, which usually
occurs due to antigenic stimulation by allergens or
helminthic (parasite) antigens.

15. Cytokines and cancer
 Cancers are a very heterogeneous group of diseases, and the
mechanisms of malignant transformation and continuation
are very diverse in different tumors.
 They represent diseases in which intercellular signalling
mechanisms have been damaged so as to remove the normal
constraints on cellular growth and replication.

16.  In many cases, cytokines form part of these control
mechanisms or induce other molecules that perform these
functions.
 For example, some proto-oncogenes and oncogenes code for
normal or abnormal components of cytokine receptor or
signal transduction pathways.

17.  Cytokines may have growth inhibitory properties directly on
cancer cells, cause tumor regression due to modification of
the host tumor relationship, or enhance anti-tumor immune
effects.
 They may also act as growth factors for malignant cells.

18.  As far as the clinical laboratorian is concerned, the
measurement of cytokines in biological fluids may be useful
for monitoring progression of some tumors and for
therapeutic monitoring when they are used as anticancer
agents.

19. Regulation of growth and differentiation
 The IFNs naturally assumed great importance in the search
for tumor-modifying cytokines in view of their growth
inhibitory properties on many cells.
 They can down-regulate the expression of cellular proto-
oncogenes such as myc, the enzymes associated with DNA
replication, and the receptors for growth factors such as EGF.

20.  In vivo they may also activate cytotoxic T cells.
 IL-6 inhibits the growth of a variety of human cell lines
derived from malignant tumors of breast, ovary, and myeloid
cells.
 IL-6 is a potent growth factor for plasmacytoma and
myeloma cells.

21. Toxicity for Tumor cells
 The mechanisms are arachidonic acid dependent and may
involve the production of oxygen free radicals that destroy
the tumor cell DNA.
 TheTNFs can inhibit tumor cell growth by a direct cytotoxic
effect, inhibit proliferation, and induce differentiation.

22.  TNF can also stimulate growth of some malignant cells.
 TNF exhibits protumor effects.

23. Immune response to tumor
 The tumor-suppressor roles of cytokines include many
regulatory effects on the immune system.
 The IFNs enhance the expression of MHC class I antigens on
many different normal and malignant cell types, making
them susceptible to killing by cytotoxic T cells.

24.  IL-2 stimulates peripheral blood lymphocytes, rendering a
subpopulation of them more cytotoxic for tumor cells.
 This subpopulation of cells is known as lymphokine-
activated killer cells (LAK cells).
 LAK cells probably form part of the NK-cell population.

25.  NK-cell population is responsible for immune surveillance of
potentially malignant cells.
 IL-2 is used therapeutically intravenously or subcutaneously
and in renal cell carcinoma, and melanoma gives responses
significantly better than chemotherapy.

26.  LAK cells may be stimulated ex vivo using lymphocytes
derived from plasmapheresis and reinfused into the patient.
 Tumor infiltrating lymphocytes (TILs) may be extracted and
stimulated.
 Significant toxicity limits the dose of IL-2.

28. Mediation of paraneoplastic effects
 A wide range of paraneoplastic effects seem to be mediated
by cytokines.
 The fever that so often accompanies cancer is mediated by
IL-6, IL-1, and TNF.
 Fever typically occurs in lymphoid malignancies in which
these cytokines are released.

29.  Anemia may be mediated by TNF, thrombocytoses by IL-6.
 Cachexia is mediated by TNF and IFNγ.
 Bone reabsorbtion and hypercalcaemia are induced by IL-1.

30. Cytokines as tumor markers
 IL-6 levels are elevated in a significant proportion of patients
with myeloma and correlate broadly with disease activity,
proliferation index, and survival.
 Patients with monoclonal gammapathies of undetermined
significance (MGUS) generally have normal or low levels of
IL-6.

31.  In Hodgkin’s disease and non-Hodgin’s lymphoma, there is a
correlation between symptoms of fever and malaise and IL-6
level.
 Elevated concentrations of the soluble IL-2 receptor (sIL-2R)
have been found in a number of malignancies of the
lymphoid system and the leukemias.

32.  In children with acute lymphoid leukemia, raised levels
predict relapse and correlate with survival.
 The use of sIL-2R measurements will have a place in the
management of the hematological malignancies.

33.  TNF expression or protein production has been
demonstrated in many cancer cell lines and biopsies.
 Serum TNF and sTNFR levels are raised in a wide range of
malignancies.
 Their measurement may be useful in follow-up studies.

34.  A high proportion of patients with hematological
malignancies have raised levels of M-CSF.
 M-CSF is a tumor marker for ovarian cancer.
 There is great interest in the use of M-CSF together with
CA125 as an index of therapy in the ovarian cancer.

35.  A number of the growth factors, such as the IGFs, PDGF, and
the TGFs, show raised serum concentratons in various
cancers.
 Serum TGFα levels is raised in breast cancer, hepatocellular
cancer.
 The TGFα urinary levels are raised in head and neck cancer.

36. Clincal significance
Rheumatoid arthritis
 It is a systemic inflammatory disease in joints and other
tissues.
 The disease is initiated, in a genetically predisposed
individual, by activation of helper T cells responding to some
arthritogenic agent, possibly a microbe.

37.  Activated CD4+ cells produce a number of cytokines that
have two principal effects:
(I) Activation of macrophages and other cells in the joint
space, which release tissue-destructive enzymes and
other factors that perpetuate inflammation, and
(I) Activation of the B-cell system, resulting in the
production of antibodies, some of which are directed
against self-constituents.

38.  The resultant auto-immune reactions damage the joints and
are believed to play an important role in disease progression.
 The rheumatoid synovium is embarassingly rich in both
lymphocye and monocytes desired cytokines.

39.  The activity of these cytokines can account for many features
of rheumatoid synovitis.
 IL-1 and TGF-β, cause proliferation of synovial cells and
fibroblasts.
 They also stimulate synovial cells and chondrocytes to
secrete proteolytic and matrix-degrading enzymes.

40.  In RA, a role for IL-15, secreted by activated T cells and
macrophages, seems prominent.
 TNF, IL-1, IL-6, IL-15, interferon-γ, and growth factors (GM-
CSF, TGF-β) as well as proteases and elastases released by
leukocytes and synoviocytes.
 TNF-α and IL-1 upregulate expression of adhesion molecules
by endothelial cells, resulting in the accumulation of white
cells in the inflammed synovium.

41.  Cartilage destruction, both at the interface with the pannus
and distant from it, is further enhanced by IL-1 and TNF-α as
these cytokines also stimulate the chondrocytes to produce
more degradative enzymes and inhibit their synthesis of
reparative proteoglycans.
 There is a sustained, irreversible cartilage destruction.

43. Septic shock
 Shock or cardiovascular collapse is the final common
pathway for a number of potentially lethal clinical events,
including severe hemorrhage, extensive trauma or burns,
large myocardial infarction, massive pulmonary embolism
and microbial sepsis.
 Shock constitutes systemic hypoperfusion due to reduction
either in cardiac output or in the effective circulating blood
volume.

44.  The end results are hypotension, followed by impaired tissue
perfusion and cellular hypoxia.
 The mononuclear phagocytes respond to lipopolysaccharides
(LPS) by producing TNF, which in turn induces IL-1
synthesis.

45.  TNF and IL-1 both act on endothelial cells to produce further
cytokines (e.g., IL-6 and IL-8), as well as induce adhesion
molecules.
 Thus, the initial release of LPS results in a circumscribed
cytokine cascade intended to enhance the local acute
inflammatory response and improve clearance of the
infection.

46.  With moderately severe infections, and therefore with higher
levels of LPS ( and a consequent augmentation of the
cytokine cascade ), cytokine-induced secondary effectors (
e.g., nitric oxide and platelet-activating factor ) become
significant.
 In addition, systemic effects of TNF and IL-1 may begin to be
seen, including fever and increased synthesis of acute-phase
reactants.

47. Tuberculosis
 Tuberculosis is a communicable chronic granulomatous
disease caused by mycobacterium tuberculosis.
 It usually involves the lungs but may affect any organ or
tissue in the body.
 Typically, the centre of tubercular granulomas undergo
caseous necrosis.

48.  The sequence of events following an initial lung infection
are
(i) Antigen from the tubercle bacillus reaches draining lymph
nodes and is presented to T cells.
CD4+ cells of the THI type are sensitized and recirculate to
the site of infection.
Critical in this initial generation of sensitized THI cells is
elaboration of IL-12 by the macrophages.

50. (ii) Sensitized CD4+ cells release cytokines when exposed to
antigen at the site of infection.
(iii) Monocytes are recruited and activated (particularly by γ-
interferon from the CD4+ cells) to kill or inhibit the growth
of the organism.

51. (iv) In response to cytokines and possibly the constituents of
the cell wall of the bacillus, some of the activated
macrophages form granulomas, which may subsequently
entrap the residual microorganisms.
(v) CD4+ helper T cells also facilitate the development of CD8+
cytotoxic T cells, which can not only kill tuberculosis-
infected macrophages but also produce IFN-γ.