cytokines /chemokines virokines/viroceptors

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Immunol Lett 2002 Oct 1;83(3):153-61 Related Articles, Links

Peptide immunomodulators versus infection; an analysis.

Dutta RC.

Discovery Laboratory, Indian Institute of Chemical Technology, Uppal Road,

Habsiguda, 500 007, Hyderabad, India

A disease gets manifested only when the host immune system is not strong

enough to fight off the infective agents. A number of small peptides both

from natural and synthetic origin are found to be capable of modulating the

immune response. While immune adjuvants are known to strengthen the immune

response and help the host not to give way to the pathogens thereby

preventing their establishment, the immunosuppressors are found useful in

autoimmune conditions as well as in facilitating the organ transplants.

Recent understanding of immune network, however, reveals its cross

connectivity with the endocrine and central nervous systems as well. Thus,

the inhibition and control of disease by planned restoration of homeostatis

in these systems through immunomodulation is also possible.

PMID: 12095705 [PubMed - in process]

J Neurosci Res 2002 Jul 1;69(1):94-103 Related Articles, Links

Cytokines, chemokines, and cytokine receptors in human microglia.

Lee YB, Nagai A, Kim SU.

Division of Neurology, Department of Medicine, University of British

Columbia, Vancouver, Canada.

Enriched populations of human microglial cells were isolated from mixed cell

cultures prepared from embryonic human telencephalon tissues. Human

microglial cells exhibited cell type-specific antigens for

macrophage-microglia lineage cells including CD11b (Mac-1), CD68, B7-2

(CD86), HLA-ABC, HLA-DR and ricinus communis aggulutinin lectin-1 (RCA-1),

and actively phagocytosed latex beads. Gene expression and protein

production of cytokines, chemokines and cytokine/chemokine receptors were

investigated in the purified populations of human microglia. Normal

unstimulated human microglia expressed constitutively mRNA transcripts for

interleukin- 1beta (IL-1beta) -6, -8, -10, -12, -15, tumor necrosis

factor-alpha (TNF-alpha), macrophage inflammatory protein-1alpha

(MIP-1alpha), MIP-1beta, and monocyte chemoattractant protein-1 (MCP-1),

while treatment with lipopolysaccharide (LPS) or amyloid beta peptides

(Abeta) led to increased expression of mRNA levels of IL-8, IL-10, IL-12,

TNF-alpha, MIP-1alpha, MIP-1beta, and MCP-1. Human microglia, in addition,

expressed mRNA transcripts for IL-1RI, IL-1RII, IL-5R, IL-6R, IL-8R, IL-9R,

IL-10R, IL-12R, IL-13R, and IL-15R. Enzyme-linked immunosorbent assays

(ELISA) showed increased protein levels in culture media of IL-1beta, IL-8,

TNF-alpha, and MIP-1alpha in human microglia following treatment with LPS or

Abeta. Increased TNF-alpha release from human microglia following LPS

treatment was completely inhibited with IL-10 pretreatment, but not with

IL-6, IL-9, IL-12, IL-13, or transforming growth factor-beta (TGF-beta).

Present results should help in understanding the basic microglial biology,

but also the pathophysiology of activated microglia in neurological diseases

such as Alzheimer disease, Parkinson disease, Huntington disease,

amyotrophic lateral sclerosis, stroke, and neurotrauma. Copyright 2002

Wiley-Liss, Inc.

PMID: 12111820 [PubMed - in process]

J Immunother 2002 Mar-Apr;25 Suppl 1:S68-71 Related Articles, Links

Plasma interleukin-18 levels in patients with psychiatric disorders.

Kokai M, Kashiwamura S, Okamura H, Ohara K, Morita Y.

Department of Neuropsychiatry, and Laboratory of Host Defenses, Institute

for Advanced Medical Science, Hyogo College of Medicine, Nishinomiya, Japan.

SUMMARY: There are an increasing number of reports on an association between

the alteration of circulating cytokine levels and pathophysiology of

psychiatric disorders. Plasma concentrations of interleukin (IL)-18 were

measured in 13 nonmedicated patients with psychiatric disorders. There was a

significant elevation of IL-18 levels in patients with major depression (n =

8) and panic disorder (n = 5), compared with normal controls. The mean IL-18

value of our psychiatric patients was comparable with that of various

somatic disorders reported. We suggest that the elevation of plasma IL-18

levels reflects the increased production and release of IL-18 in the central

nervous system under stressful settings. We propose that the measurement of

IL-18 plasma levels may provide a useful index for the involvement of immune

system in psychiatric disorders.

PMID: 12048354 [PubMed - in process]

J Neuropathol Exp Neurol 2002 Jul;61(7):614-22 Related Articles, Links

Neutralizing antibodies to IL-18 ameliorate experimental autoimmune neuritis

by counter-regulation of autoreactive Th1 responses to peripheral myelin

antigen.

Yu S, Chen Z, Mix E, Zhu SW, Winblad B, Ljunggren HG, Zhu J.

Department of NEUROTEC, Karolinska Institutet, Huddinge University Hospital,

Stockholm, Sweden.

Experimental autoimmune neuritis (EAN) is a demyelinating disease of the

peripheral nervous system (PNS). This acute inflammatory disease is mediated

by CD4+ T cells and bears significant similarities to the Guillain-Barre

syndrome of humans. In the present study, we investigated the function of

IL-18 in T cell-mediated autoimmunity of EAN in mice induced by P0 peptide

180-199 and Freund's complete adjuvant. Our data indicate that in 2

different therapeutic regimens, anti-IL-18 monoclonal antibody (mAb)

effectively ameliorates the clinical and pathological signs of EAN. The

suppression is associated with reduced inflammatory cell infiltration into

the PNS and an insufficiency of autoreactive Th1 cells, as reflected by a

reduced mononuclear cell proliferation and IFN-gamma-secretion in the

spleen. Increased numbers of IL-4 expressing cells and decreased numbers of

IFN-gamma and TNF-alpha expressing cells were found in the PNS. Our results

suggest that shifting the Th1/Th2 balance towards Th2 cells may be one

mechanism underlying EAN suppression by anti-IL-18 mAb. In addition,

anti-IL-18 mAb treatment reduced anti-P0 peptide 180-199 autoantibody

responses, which may also contribute to EAN suppression. We conclude that

endogenous IL-18 plays a critical role in the pathogenesis of autoimmune

demyelinating disease of the PNS and that IL-18 antagonists may provide a

new therapy for these diseases.

PMID: 12125740 [PubMed - indexed for MEDLINE]

Genome Biol 2002 Jul 29;3(8):REVIEWS3011 Related Articles, Links

Toll-like receptors: a family of pattern-recognition receptors in mammals.

Armant MA, Fenton MJ.

Pulmonary Center, Boston University School of Medicine, Boston, MA

02118-2394, USA. mfenton@...

Toll-like receptors are a family of pattern-recognition receptors in mammals

that can discriminate between chemically diverse classes of microbial

products, including bacterial cell-wall components, and that can elicit

pathogen-specific cellular immune responses. Toll-like receptors share

characteristic features with the interleukin-1 and interleukin-18 cytokine

receptors and these receptor classes activate similar signal-transduction

pathways.

PMID: 12186654 [PubMed - in process]

Nat Immunol 2001 Aug;2(8):675-80 Related Articles, Links

Toll-like receptors: critical proteins linking innate and acquired immunity.

Akira S, Takeda K, Kaisho T.

Department of Host Defense, Research Institute for Microbial Diseases, Osaka

University, Osaka 565-0871, Japan. sakira@...

Recognition of pathogens is mediated by a set of germline-encoded receptors

that are referred to as pattern-recognition receptors (PRRs). These

receptors recognize conserved molecular patterns (pathogen-associated

molecular patterns), which are shared by large groups of microorganisms.

Toll-like receptors (TLRs) function as the PRRs in mammals and play an

essential role in the recognition of microbial components. The TLRs may also

recognize endogenous ligands induced during the inflammatory response.

Similar cytoplasmic domains allow TLRs to use the same signaling molecules

used by the interleukin 1 receptors (IL-1Rs): these include MyD88,

IL-1R--associated protein kinase and tumor necrosis factor

receptor--activated factor 6. However, evidence is accumulating that the

signaling pathways associated with each TLR are not identical and may,

therefore, result in different biological responses.

Publication Types:

Review

Review, Tutorial

PMID: 11477402 [PubMed - indexed for MEDLINE]

Clin Exp Immunol 2002 Sep;129(3):510-8 Links

T-cells in the cerebrospinal fluid express a similar repertoire of

inflammatory chemokine receptors in the absence or presence of CNS

inflammation: implications for CNS trafficking.

Kivisakk P, Trebst C, Liu Z, Tucky BH, SOrensen TL, Rudick RA, Mack M,

Ransohoff RM.

Department of Neurosciences, Lerner Research Institute, Cleveland Clinic

Foundation, Cleveland, OH, USA.

It is believed that chemokines and their receptors are involved in

trafficking of T-cells to the central nervous system (CNS). The aim of the

current study was to define the expression on cerebrospinal fluid (CSF)

T-cells of six chemokine receptors associated with trafficking to sites of

inflammation. Flow cytometry was used to detect chemokine receptor

expression. We observed that CD3+T-cells in the CSF express a restricted

array of inflammatory chemokine receptors, specifically CXCR3, CCR5 and

CCR6, but little CCR1-3. This repertoire was independent of the presence of

CNS inflammation, since comparable findings were obtained in patients with

multiple sclerosis (MS) and individuals with non-inflammatory neurological

diseases. The enrichment of CCR5+T-cells in the CSF could largely be

explained by higher frequency of CD4+/CD45RO+T-cells in this compartment. In

contrast, CD4+/CD45RO+T-cells expressing CXCR3 were significantly enriched

in CSF as compared with blood. Similar levels of CCR6+/CD3+T-cells were

observed in blood and CSF, while levels of CCR2+/CD3+T-cells were lower in

CSF than in blood. The CSF was virtually devoid of CCR5+/CXCR3- T-cells,

suggesting that the expression of CCR5 alone is not sufficient for the

trafficking of CD3+T-cells to the CSF. We hypothesize that CXCR3 is the

principal inflammatory chemokine receptor involved in intrathecal

accumulation of T-cells in MS. Through interactions with its ligands, CXCR3

is proposed to mediate retention of T-cells in the inflamed CNS.

PMID: 12197893 [PubMed - in process]

New Microbiol 2002 Jul;25(3):335-40 Related Articles, Links

Modulatory effect of HHV-6 on MCP-1 production by human monocytes.

Arena A, Stassi G, Speranza A, Iannello D, Mastroeni P.

Department of Surgical Sciences, Policlinico Universitario, University of

Messina, Italy.

Chemokines represent a large family of proinflammatory proteins that

orchestrate leukocyte trafficking to sites of viral infection. Human Herpes

virus type 6 (HHV-6) is a typical immunosuppressive agent, as suggested by

its tropism. In this study the production of monocyte chemoattractant

protein-1 (MCP-1) and interleukin-10 (IL-10) by human peripheral blood

monocytes was evaluated during HHV-6 infection. Our results demonstrate that

HHV-6 infection triggers monocytes to release MCP-1 and IL-10. The addition

of exogenous recombinant MCP-1 upregulates the release of extracellular

virus, whereas does not influence the percentage of viral-antigen positive

cells. Furthermore, the addition of monoclonal antibodies anti-IL-10

down-regulates MCP-1 release induced by HHV-6. These findings indicate that

IL-10 and MCP-1 production was closely related and that the marked amounts

of MCP-1 were supported not only by virus but also by virus-induced IL-10.

PMID: 12173776 [PubMed - in process]

Clin Immunol 2002 Jun;103(3 Pt 1):309-16 Related Articles, Links

gamma/delta T cells in multiple sclerosis: chemokine and chemokine receptor

expression.

Murzenok PP, Matusevicius D, Freedman MS.

Division of Neurology, Ottawa Hospital General Campus, University of Ottawa,

Canada.

gamma/delta T cells are enriched in multiple sclerosis (MS) brain lesions

and have been postulated to contribute to the pathogenesis of the disease.

Increased expression of the chemokine receptors CCR5 and CXCR3 on T cells

and raised amounts of the chemokines RANTES and IP-10 have been noted in the

CSF and brain tissue of MS patients, but the contribution of gamma delta T

cells to these increases is unknown. We therefore compared intracellular

RANTES and IP-10 production as well as CCR5, CXCR3, and CXCR1 expression by

gamma delta T cells derived from the blood and CSF of patients with MS and

healthy controls (HC). We observed higher RANTES production by MS gamma

delta than by alpha beta T cell lines. Most of the MS as well as the HC

gamma delta and alpha beta T cell lines expressed CXCR3, while expression of

CXCR1 was low. Interestingly, MS gamma delta T cell lines, compared to lines

from HC, expressed lower levels of CCR5. Furthermore, CSF-derived gamma

delta T cells had even lower CCR5 expression than blood-derived ones. The

higher RANTES production by MS gamma delta T cell lines, together with a

lower expression of CCR5, may reflect an autoregulatory loop, caused by an

increased production of its ligands (RANTES, MIP-1 alpha, and MIP-1 beta) or

due to other pro-inflammatory cytokines. Alternatively, we show that lower

CCR5 expression could also reflect the result of repeated in vivo

stimulation of gamma delta T cells by autoantigens.

PMID: 12173306 [PubMed - indexed for MEDLINE]

Biol Chem 2002 Aug 14; [epub ahead of print] Links

Tyrosine-sulfated peptides functionally reconstitute a CCR5 variant lacking

a critical amino-terminal region.

Farzan M, Chung S, Li W, Vasilieva N, Schnitzler CE, Marchione RJ, Gerard C,

Gerard NP, Sodroski J, Choe H.

Dept. of Pediatrics, Children's Hospital, Boston, MA 02115.

Entry of most primary HIV-1 isolates into their target cells requires the

cellular receptor CD4 and the G protein-coupled chemokine coreceptor CCR5.

An acidic, tyrosine-rich, and tyrosine sulfated domain of the CCR5

amino-terminus plays a critical role in the ability of CCR5 to serve as an

HIV-1 coreceptor, and tyrosine sulfated peptides based on this region

physically associate with the HIV-1 envelope glycoprotein gp120 and slow

HIV-1 entry into CCR5-expressing cells. Here we show that the same tyrosine

sulfated peptides, but not their unsulfated analogs, can restore the HIV-1

coreceptor activity of a CCR5 variant lacking residues 2-17 of its

amino-terminus. Additionally, these sulfated peptides restored the ability

of this CCR5 variant to mobilize calcium in response to the chemokines

MIP-1a and MIP-1b. These observations show that a tyrosine-sulfated region

of the CCR5 amino terminus can function independently to mediate association

of chemokines and the HIV-1 envelope glycoprotein with the remaining domains

of CCR5.

PMID: 12183462 [PubMed - as supplied by publisher]

(From Cope cytokines)

Virokine

[ viral cytokine ] A collective term proposed to describe virus-encoded

proteins which counteract host responses, act like secreted mimics of host

ligands (Cytokines ) and possess mainly immunosubversive activities. These

viral genes are thought to have been captured from host cells during viral

evolution and modified to confer an advantage in viral replication, survival

or transmission. Analysis of various viral proteins demonstrates that these

virus-encoded proteins are often smaller and more powerful than the highly

homologous host immune proteins.

Examples of virus-encoded cytokine mimics or factors involved in cytokine

processing are:

Factor Source Function

14.7 kDa orf virus protein orf virus behaves like VEGF

16 kDa orf virus protein orf virus behaves like VEGF

38K gene of Cowpox virus Cowpox virus inhibitor of IL1-beta Convertase

BCRF-1 Epstein-Barr virus viral IL10

CGF Cowpox virus similar to vaccinia virus VGF

cmvIL10 cytomegalovirus viral IL10

Herpesvirus glycoprotein D Herpes simplex virus binding of TNF-beta ,

LIGHT

HJ1 cytomegalovirus viral homologue of chemokines

HVS13 Herpesvirus saimiri viral IL17

ICP34.5 herpes simplex virus similar to MyD116

MC148R molluscum contagiosum virus blocking of MIP-1-alpha , CCR8

antagonist

MGF Myxoviruses EGF TGF-alpha related

LMW23-NL African swine fever virus similar to MyD116

sis simian sarcoma virus PDGF homologue

orf virus IL10 orf virus viral IL10 homologue

Poxvirus growth factor Poxviruses EGF like

RSV Glycoprotein G respiratory syncytial virus functions of Fractalkine

SERP-1 Myxoma and Pox viruses secreted serine protease

serp2 Myxoma virus inhibitor of IL1-beta Convertase

SFGF Shope fibroma virus EGF like

tat protein HIV multifunctional VEGF homolog, integrin ligand, homolog of

chemokines

U83 HHV-6 homologue of chemokines

Vaccinia 19 kDa protein Vaccinia virus EGF like

viral IL6 KSHV viral IL6 homologue

viral IL8 Marek's disease virus viral IL8 homologue

viral IL17 Herpesvirus saimiri viral IL17 homologue

viral MIP-1-alpha KSHV viral MIP-1-alpha homologue

viral MIP-2 KSHV viral MIP-2 homologue

viral MIP-3 KSHV a chemokine homologue

VEGF-E parapoxvirus Orf virus viral VEGF homologue

Virus-encoded factors appear to affect the activities of cytokines in at

least four different ways: ( a) by inhibiting the synthesis and release of

cytokines from infected cells;

(b ) by interfering with the interaction between cytokines and their

receptors;

(c ) by inhibiting signal transmission pathways of cytokines ;

(d) by synthesizing virus-encoded cytokines that antagonize the effects of

host cytokines mediating antiviral processes.

Viroceptor

A term proposed to describe virus-encoded homologs of cellular receptors of

cytokines (cytokine receptor mimics ). These homologs are found in a number

of viruses, particularly in members of the poxvirus, herpesvirus and

retrovirus families and are thought to derive from captured and modified

cellular genes. Some of the factors listed here appear to be proteins

unrelated to known cellular proteins.

Most of these receptor homologs are either secreted glycoproteins or are

located at the infected cell surface. It is believed that the function of

these viral receptor mimics is to intercept the activity of the cognate

cytokine, thus effectively short-circuiting host immune responses to the

viral infection.

Examples of genuine viroceptors or of virus-encoded proteins involved in

cytokine receptor-associated processes are:

Factor Source Function

B8R vaccinia virus receptor for IFN-gamma

B15R vaccinia virus binding to IL1-beta

B18R vaccinia virus receptor for IFN-alpha

BARF1 Epstein-Barr virus binding to M-CSF

crmB cowpox virus binding to TNF-alpha , TNF-beta

crmC cowpox virus inhibition of TNF responses

crmD cowpox virus binds to TNF-alpha , LT-alpha

crmE cowpox virus binds to TNF and TNF-related proteins

ECRF-3 Herpesvirus saimiri receptor for chemokines IL8 , MGSA , NAP-2

EHV-2 E1 ORF Equine herpesvirus 2 binding of eotaxin

G5R Variola virus binding of Beta-Chemokines

GIF orf virus binding of GM-CSF and IL2

M3 murine gammaherpesvirus 68 binding of chemokines

M11L Myxoma virus binding of cytokines

MC54L molluscum contagiosum virus binding to IL18

M-T1 Myxoma virus binding of chemokines , RANTES

M-T7 Myxoma virus binding to IFN-gamma

ORF-74 Herpesvirus KSHV IL8 receptor

p13 ectromelia virus IL18 receptor

Tanapoxvirus 38 kDa protein Tanapoxvirus binding to IFN-gamma , IL2 , IL5

T2 Myxoma virus binging to TNF-alpha , TNF-beta

U12 human herpesvirus 6 binding to various chemokines

U51 human herpesvirus 6 binding to various chemokines

US28 Cytomegalovirus binding to various chemokines

vCCI Variola virus binding to Beta-Chemokines

vCKBP Vaccinia virus binding to various chemokines

vIL18BP vaccinia, ectromelia and cowpox virus binding to IL18

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