Cytokines are proteins involved in cell signaling and communication that are important in immune responses and inflammation. They are produced by immune cells and modulate processes like immune cell development, activation of lymphocytes and phagocytes, and the inflammatory response. Cytokines play roles in diseases like cancer, rheumatoid arthritis, sepsis, and tuberculosis by influencing processes such as immune cell recruitment and activation, tissue damage, and granuloma formation. Their levels can provide information about disease activity and progression in some conditions.

1. M.Prasad Naidu
MSc Medical Biochemistry,
Ph.D.Research Scholar

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.