Cytokines Online Pathfinder Encyclopaedia

http://www.copewithcytokines.de/cope.cgi

The term cytokine, or Immunocytokines , was used initially to separate a group of immunomodulatory proteins, called also Immunotransmitters , from other Growth factors that modulate the proliferation and bioactivities of non-immune cells.

Some cytokines are produced by a rather limited number of different cell types while others are produced by almost the entire spectrum of known cell types.

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In the more restricted sense cytokines comprise

Interleukins , initially thought to be produced exclusively

by leukocytes, Lymphokines , initially thought to be prod

uced exclusively by lymphocytes, Monokines , initially th

ought to be produced exclusively by monocytes,

interferons, initially thought to be involved in antiviral re

sponses, colony stimulating factors, initially thought to su

pport the growth of cells in semi-solid media,

Chemokines , thought to be involved in Chemotaxis , and

a variety of other proteins.

Cyto: cell-kines: kinesis, 可移動 , 分裂

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Established cell lines that entirely depend for their survival and proliferation on the continuous presence of one or more of growth factors . Factor-dependent cell lines are capable of continuous growth in the presence of the growth factors and cytokines they require

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Hematopoiesis: Greek haima for blood and poiein, to make

Hematopoiesis is the dynamic and complex developmental process of the formation of new blood cells.

An early intra-embryonic site of hematopoiesis is found in the Paraaortic splanchnopleura and in a structure termed AGM ( abbr. for aorta, gonads, and mesonephros) ( Nishikawa et al). mice and birds

Hematopoiesis taking place prior to the development of the fetal liver is referred to as primitive hematopoiesis . The fetal liver is the site of definitive hematopoiesis early during embryonal development.

The bone marrow with its intersinusoidal spaces is the site responsible for the generation of blood cells in the post-natal phase.

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Hematopoesis

Sites of blood cell formation Embryo: yolk sac

Fetus: spleen and liver

Adult: “bone marrow” sternum, ribs, pelvis, cranium, vertebrae, long bones (tibia and femur)

www.wsu.edu/~ms523/ ms523s198.html

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The high proliferative potential colony assay

Bone marrow cells 25000 cells of Balb/c, after 150 mg/kg of 5-Fu.

Culture s are incubated under low oxygen tension for 12 days and scored for HPP-CFU.

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The development of neutrophils from the stem cell stage

Moore, 10:2719

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http://www.whfreeman.com/immunology/CH03/hematopoiesis.htm

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In the presence of infection, cytokines produced by activated macrophages and T-helper cells induce additional hematopoietic activity, resulting in rapid expansion of white blood cells that participate in fighting infection.

http://www.whfreeman.com/immunology/CH03/hematopoiesis.htm

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Mosmann TR et al , J Immunol (1986) 136:2348-2357

This is underscored by the uniform phenotype of our anti-CRBC T cell lines, which were all Th1. Only when we examined T cell clones specific for FGG or alloantigens did we discover antigen-specific T cells of the Th2 cells

Th2 cells produce activities that strongly enhance IgE/IgG1 production....., whereas Th1 cells produce interferon-g, which strongly inhibits the enhancing activities in Th2 supernatants .....

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Two types of murine helper T cell clone Mosmann TR et al , J Immunol (1986) 136:2348-2357

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Cytokine secretion phenotypes of mouse T cells

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Immunosuppresive cytokines

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Th1 and Th2 cell generation is regulated by the equilibrium between different groups of cytokines, with dominant effects of IL-12 and IL-4 (with feed back mechanisms)

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The commitment of TH0 cells to become TH1 or TH2 is influenced by cytokines secreted by the 2 subtypes themselves and by macrophages , NK cells and mast cells.

http://www.brown.edu/Courses/Bio_160/Projects1999/ies/cytok.html

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Cytokine soup during disease

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A Th1 to Th2 switch ia a critical step in the etiology of HIV infection

Clerici M and Shearer GM, Immunol Today 14:107-111 (1993)

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Becoming a paradigm for disease management

Susceptibility to Leishmania major infection in interleukin-4-deficient mice. Noben-Trauth et al 1996, Science 271:987-989

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Induction of Th1 and Th2 responses: a key role for the natural immune respones?

Immunol Today 13:379-381 (1992)

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Role of IL-12 in the generation of Th1 cells

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Cytokine responsiveness in a human volun

teer injected with LPS. TNF-a rises almost i

mmediately and peaks at 1.5 hours; the sha

rp decline of TNF-a may be due to modulati

on by its soluble receptor sTNF-R. A secon

d wave of cytokines that peaks at 3 hours a

ctivates the acute phase response in the liv

er and the systemic pituitary response (bot

h via IL-6) and the activation and chemotaxi

s of neutrophils (via IL-6, IL-8 and G-CSF).

Pituitary-derived adrenocorticotropic horm

one (ACTH) and migration inhibition factor

(MIF) peak at 5 hours and coincide with pea

k levels of the regulatory cytokines IL-Ra a

nd IL-10 that counteract the release or activ

ity of proinflammatory cytokines.

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IL-4 instructs TH1 responses and resistance to Leishmania major in susceptible BALB/c miceBiedermann T et al. 2001, Nature Immunol 2:11

• When present during the initial activation of dendritic cells (DCs) by infectious agents, IL-4 instructed DCs to produce IL-12 and promote TH1 development. This TH1 response established resistance to Leishmania major in susceptible BALB/c mice. When present later, during the period of T cell priming, IL-4 induced TH2 differentiation and progressive leishmaniasis in resistant mice. Because immune responses developed via the consecutive activation of DCs and then T cells, the contrasting effects of IL-4 on DC development and T cell differentiation led to immune responses that had opposing functional phenotypes.

As usual, things may not be so simple

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IL-4 instructs DCs to produce increased amounts of IL-12 and to promote TH1 development in vitro.

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IL-4 instructs resistance to L. major in susceptible BALB/c mice. Groups of five BALB/c mice or more were inoculated in one hind footpad with 2×105 stationary phase L. major promastigotes either of strain LV39, MRHO/Sv/59/P (a) or strain MHOM/IL/81/FE/BNI (b).

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IL-4 instructs parasite containment in susceptible BALB/c mice.BALB/c mice were infected with L. major and treated twice with the indicated doses of IL-4 or NMS during the first 8 h of infection. After 9 weeks, the number of viable parasites in infected tissues was estimated using a parasite-limiting dilution assay.

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IL-4 treatment during the first 8 h of L. major infection instructs IL-12–pro

ducing DC1s and suppresses IL-4 expression. Control mice (Control and I

L-4) or mice infected with L. major promastigotes (3×106) were treated eit

her with NMS or twice with 1.0 μg of IL-4 at 0 and 8 h of infection.

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Induction of TH1 responses with IL-4 depends on IL-12. BALB/c mice were infe

cted with L. major and treated twice with IL-4 (at 0 and 8 h) and either NMS or a

nti–IL-12. After 8 weeks, popliteal lymph node cells were isolated, RNA extract

ed and expression of IL-4 and IFN-γ mRNA determined by semi-quantitative R

T-PCR. (a) The relative changes in IL-4 and IFN-γ mRNA were normalized to the

values in control infected BALB/c mice, arbitrarily fixed as 100. (b) The ratio of

IL-4:IFN-γ mRNA for each experimental group was determined. L. major infecti

on, cytokine treatment and mRNA analysis were done.

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Treatment with anti–IL-12 abrogates IL-4–induced resistance to L. major in BALB/c mice. Mice were infected with L. major promastigotes and treated with either NMS (open circles) or twice with 1.0 μg of IL-4 (at 0 and 8 h) and either NMS (filled squares) or the IL-12 mAbs C17.8 and C17.15 (open triangles) 12 and 3 h before infection. One of two similar experiments is shown. Infection, cytokine treatment and weekly monitoring of footpad lesions were done .

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Extension of IL-4 treatment into the period of T cell priming reverses IL-4–induced resistance to L. major. Three groups of mice were infected and treated with either 1.0 μg of IL-4 or NMS. The first L. major–infected group received NMS (open circles), the second 1.0 μg of IL-4 at 0 and 8 h (filled squares) and the third 1.0 μg of IL-4 at 0, 8, 16 and 24 h (crosses). Infection, cytokine treatment and weekly monitoring of footpad lesions were done .

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Timing determines whether IL-4 treatment instructs a TH1 phenotype and resistance or a TH2 phenotype and susceptibility to L. major in TCR Vβ4-deficient mice. (a,b) After parasite inoculation,Vβ4-deficient BALB/c mice were treated during the first 64 h with either eight injections of PBS–1% NMS or eight injections of 0.1 μg of IL-4 (total amount: 0.8 μg). Alternatively, mice were treated twice during the first 8 h of infection with 1.0 μg of IL-4 as in Fig. 2. Eight weeks after infection, cells from draining lymph nodes were stimulated in vitro with ultraviolet-irradiated parasites and cytokines were determined in the supernatants as described (see Methods). The IL-4:IFN-γ ratio was 3.71 in mice that received IL-4 over 64 h and 0.37 in mice that received two injections of IL-4 at 0 h and 8 h. (c).

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How Th1/2 cytokines are regulated?• Transcriptional regulation of Th1/Th2 polarization, Jyothi Rengaraj

an J et al 2000, Immunol Today 21:479

The two polarized T helper (Th) subsets Th1 and Th2 are identified by their signature cytokines, interferon- (IFN-) and interleukin 4 (IL-4) respectively. Understanding the transcriptional regulation of cytokine expression is therefore critical for elucidating the process of Th cell differentiation. Ubiquitous and tissue-specific transcription factors, as well as chromatin remodeling of genomic loci have been implicated in IL-4 and IFN- regulation.

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Class I cytokine receptor family (Hematopoietin recetor)

this family includes receptors for growth hormone and prolactin.  There are conserved amino acid sequence motifs in the extracellular domain - 4 positionally conserved cysteine residues (CCCC) and a conserved sequence of Trp-Ser-X-Trp-Ser (WSXWS) where X is a nonconserved amino acid.  The receptors consist of 2 polypeptide chains:  a cytokine-specific subunit and a signal-transducing subunit which is usually not specific for the cytokine. 

http://www.umdnj.edu/pathnweb/genpath/lec_1/Class_I_Cytokine_Receptors/class_i_cytokine_receptors.htm

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Class II cytokine receptor family(Interferon receptor family)

The ligands for these receptors are the three interferons a, ß, and .  These receptors possess the conserved cysteine motifs, but lack the WSXWS motif present in class I cytokine receptors.

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Overview of Th cell differentiation. A naive CD4 T cell is activated via the TCR when it encounters antigen presented by an antigen presenting cell.

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GATA3, a zinc finger protein that was originally identified as binding the TCRa gene enhancer via a WGATAR sequence.

T-bet (T-box expressed in T cells) is a member of the T-box family of transcription factors that regulate several developmental processes. T-bet expression strongly correlates with IFN- expression.

Regulation at transcriptional level

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(a) IL-4 regulatory regions: the IL-4 proximal promoter with cis and trans elements and map of IL-4 locus showing DNAse I HSs.

(b) IFN- regulatory region and map of locus with DNAse I HS sites.

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Striking a balance: GATA3 and T-bet – model for Th1/Th2 polarization. Signals through the TCR and cytokine receptors can lead to the initiation of a Th1 program (via Stat4 activation) and the induction of T-bet, which promotes Th1 lineage commitment. Signals that favor the activation of Stat6 induce GATA3 leading to Th2 differentiation. c-Maf is then upregulated leading to increased IL-4 production and Th2 polarization.

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More than immunoregulatroy actions

Cytokine regulation of neuronal differentiation of hippocampal pr

ogenitor cells (Mehler MF et al. 1993, Nature 362:62-65.)

The signalling mechanisms governing haematolymphopoiesis and t

hose regulating neural development may be closely related, as indi

cated by similarities of higher-order structure and function of the

cytokines involved, of the regional and temporal regulation of thei

r transcription and translation, and of their bioactivity.

The mechanisms regulating lineage commitment and cellular diffe

rentiation in the neural and haematopoietic systems are similar.

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Electrophysiological analysis of the effects of growth factor treatment on neuronal maturation

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Morphological and immunocytochemical indices of progressive neuronal maturation

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Immune System and the BrainEstrogen, microglia and the IBB The microglial-cytokine--estrogen mediated network is described as a major player in the brain including the Immune Brain Barrier. One of the functional areas involved maybe the role that microglia could play in synaptic plasticity.

http://info.med.yale.edu/obgyn/reproimmuno/projects/immune.htmlFor lecture only; BC Yang

Combinatorial signal by inflammatory cytokines and chemokines mediate leukocyte interactions with extracell

ular matrix

Vaday GG et al. 2001, J leukoc Biol 69:885-892For lecture only; BC Yang

limitations of cytokines for therapeutic use

High local concentrations of cytokines during immune response cannot be mimicked clinically

Short half-life of cytokines Pleiotropic effects can cause unpredictab

le side-effects

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