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Posts Tagged ‘Differentiation’

TLR3- Cluster of Differentiation 283

Toll-like receptor 3 (TLR3) often designated as CD283 (cluster of differentiation 283) is a type I transmembrane receptor protein. It belongs to a family of evolutionary conserved innate immune recognition molecules and recognizes double-stranded RNA, a molecular pattern associated with viral infections. Like all other members of the TLR family, TLR3 is composed of an extracellular domain containing multiple leucine-rich repeats (LRRs), a transmembrane region, and a cytoplasmic tail containing the conserved TIR domain. The transmembrane domain consists of a single alpha-helix spanning the membrane, while the TIR domain is made up of a five-stranded beta-sheet surrounded by five alpha-helices. The human TLR3 ectodomain structure at 2.1 angstroms reveals a large horseshoe-shaped solenoid assembled from 23 LRRs (1). The TLR3 gene maps to chromosome 4q35 and its sequence encodes a putative 904 amino acid protein and a calculated molecular weight of 97 kDa. TLR3 is most closely related to TLR5, TLR7, and TLR8, each with 26% overall amino acid sequence identity. In vivo, two different sized transcripts for TLR3 are observed suggesting that the mRNA is alternatively spliced to generate two different forms of the protein.

TLR3 mRNA is expressed at highest levels in placenta and pancreas. There are conflicting reports regarding the expression of TLR3 in particular leukocyte populations. Some suggest that TLR3 is only expressed by dendritic cells while others find that TLR3 is expressed by T or NK cells. In vitro, PMA-differentiated THP-1 TLR3 is moderately upregulated by autocrine IFN-γ, IL-1ß, IL-6, IL-10, and TNF-α. Further, TLR3 mRNA is elevated after exposure to Gram-negative bacteria and to an even greater extent in response to Gram-positive bacteria. Ex vivo, TLR3 expression is elevated in both monocytes and granulocytes upon exposure to Gram-negative bacteria. TLR3 is usually localized intracellularly, perhaps to the lysosomal compartment or at the cell surface. However the localization of TLR3 is cell type dependent.

Human TLR3 recognizes foreign-derived double-stranded RNA of certain viruses like influenza, endogenous necrotic cell RNA and polyinosinic acid as ligands. Stimulation of the receptor by the ligand induces the activation of NF-kappaB and the production of type I interferons (IFNs) which signal other cells to increase their antiviral defenses (2). TLR3 relies on a TIR domain-containing adaptor inducing IFN-beta (TRIF)-mediated pathway for the production of IFN- in response to pathogen recognition. Trif contains a RIP homotypic interaction motif (RHIM) at the C terminus that is essential for binding of RIP1 and RIP3, two serine-threonine kinases linked to tumor necrosis factor (TNF)−mediated NF-B activation. (3, 4, 5). Activation of TLR3 leads to recruitment of receptor-interacting protein 1, TRAF3 and TRAF6, which activates TRAF family member-associated NF-B activator-binding kinase 1 (TBK1) andr inducible IB kinase (IKK-i), which directly phosphorylate IRF3 and IRF7 for the production of type-I IFN cytokines.(6)

TLR3 has been implicated in various viral infections of the respiratory tract and in central nervous system (CNS) diseases. On the contrary it positively contributes to the immune response to invading encephalomyocarditis virus. TLR3 has also been implicated in the protection against herpes simplex virus type 2 infection of the female genital tract. Recent work on TLR3 reveals its role in the immunobiology of skeletal muscle (7).

Reference:

1. J Endotoxin Res. 2006; 12(6):375-8

2. Nature. 2001 Oct 18; 413(6857):732-8

3. Nature Immunology 5, 503 – 507 (2004)

4.Rock, F.L. et al. (1998) Proc. Natl. Acad. Sci. USA 95:588.

5. Science. 2005 Jul 22; 309(5734):581-5. Epub 2005 Jun 16

6.Oncogene (2008) 27, 181–189; doi:10.1038/sj.onc.1210906

7. Clinical Microbiology Reviews, January 2008, p. 13-25, Vol. 21, No. 1

About Author
IMGENEX India Pvt Ltd. the only biotech company in Orissa and one of its kinds in Eastern India. IMGENEX India started in Oct as an outsourcing branch of IMGENEX Corporation, San Diego, USA. Find out more information about Toll-like receptors .

TLR2- Cluster of Differentiation 282

Toll-like receptor 2 (TLR2), often designated as CD282 (cluster of differentiation 282) is a type I transmembrane protein belonging to the large homologous family of Toll like receptors. TLR2 acts as functional receptor for both Gram-positive and Gram-negative bacteria. Like all other members of the TLR family, TLR2 is composed of an extracellular domain containing multiple leucine-rich repeats (LRRs), a transmembrane region, and a cytoplasmic tail containing the conserved TIR domain. TLR2 maps to chromosome 4q31-32 and encodes a putative 784 amino acid protein with 19 N-terminal LLRs and a calculated molecular weight of 84 kDa (1, 2, 3). Comparison of the amino acid sequence reveals that TLR2, TLR1, and TLR6 form a TLR subfamily, which presumably diverged from one common ancestral gene. In humans, TLR10 is also a member of this TLR2 subfamily. Among all TLR, TLR1 and TLR6 have the highest identity of overall amino acid sequence, which is 66%, and a similar genomic structure and thus it is assumed that they are the evolutionary products of gene duplication.

 

In vivo transcripts for TLR2 are observed suggesting that the mRNA is alternatively spliced. TLR2 mRNA expression is observed in brain, heart, lung, and spleen tissues and is highest in PBLs, specifically those of myelomonocytic origin. In vitro PMA-differentiated THP-1, TLR2 is most significantly upregulated by autocrine IL-6 and TNF-α, IL-1β, and IL-10. Further, TLR2 mRNA expression is elevated after exposure to both Gram-positive and Gram-negative bacteria. The increase in TLR2 expression in monocytes and granulocytes on exposure to Gram-negative bacteria is only very modest. Furthermore, TLR2 appears to be up-regulated on mononuclear cells during disorders such as chronic obstructive pulmonary disease, influenza virus infections, and sepsis

 

TLR2 act as signal transducers for various bacterial components which include lipoproteins derived from M. tuberculosis, Borrelia burgdorfei, Treponema pallidium and Mycoplasma fermentans. In addition, TLR2 mediates cellular responses to a wide variety of infectious pathogens and their products which include yeast cell walls, whole mycobacteria, mycobacterial ara-lipoarabinomannan, whole Gram-positive bacteria, peptidoglycan (PGN), Treponema glycolipid and Trypanosoma cruzi glycophosphatidylinositol anchor. TLR2 forms heterodimers with TLR1, TLR6 and possibly TLR10, where each complex is particularly sensitive to subsets of TLR2-associated pathogen-associated molecular patterns (PAMPs). It has been studied that TLR6 and TLR2 function together to detect Gram-positive bacteria, PGN and zymosan, whereas TLR2 functions either alone or with TLRs other than TLR6 to detect bacterial lipopeptides. More recent studies have suggested that, like TLR4, TLR2 complexes require CD14 and MD-2 for detection of PAMPs and signaling. (4, 5) Upon ligand recognition, TLR2 recruits both the TIR domain-containing sorting adaptor TIRAP and the signaling adaptor MyD88, and initiates the MyD88-dependent pathway. The MyD88-dependent pathway activates nuclear factor (NF)-κB, activator protein-1 (AP-1) and interferon regulatory factor 5 (IRF5), which induce inflammatory cytokine expression such as IL-6, IL-12, and TNFα. (6)

 

Aside from detection of non-self patterns, TLR2 complexes are also capable of detecting altered self patterns, such as those displayed by necrotic cells. Further, recent evidence indicates that TLR2 is recruited to phagosomes and may be directly involved in the internalization of microbial products by cells.

 

Reference:

1. Rock, F.L. et al. (1998) Proc. Natl. Acad. Sci. USA 95:588.

2. Chaudhary, P.M. et al. (1998) Blood 91:4020.

3. Dunne, A. & L.A.J. O’Neill (2003) Sci. STKE 2003:re3.

4. Modlin, R.L. (2002) Ann. Allergy Asthma Immunol. 88:543.

5. J Endotoxin Res. 2000;6(5):401-5

6. Annual Review of Biochemistry Vol. 76: 447-480 (Publication date July 2007)

About Author
IMGENEX India Pvt Ltd. the only biotech company in Orissa and one of its kinds in Eastern India. IMGENEX India started in Oct as an outsourcing branch of IMGENEX Corporation, San Diego, USA. Find out more information about Toll-like receptors .

TLR8- Cluster of Differentiation 288

Toll-like receptor 8 (TLR8) often designated as CD288 (cluster of differentiation 288) is a member of evolutionarily conserved Toll-like receptor family which are critical parts of the evolutionarily conserved innate immune system. TLR8 has been identified as natural receptor for single-stranded RNA, and is thought to act as potent activator of innate immune responses upon viral infections. Like all other members of the TLR family, TLR8 is composed of an extracellular domain containing multiple leucine-rich repeats (LRRs), a transmembrane region, and a cytoplasmic tail containing the conserved TIR domain. The TLR8 sequence encodes a 1041 amino acid protein containing 26 N-terminal leucine rich repeats with a calculated molecular weight of 120 kDa. The gene for TLR8 has been mapped to chromosome Xp22. TLR8 is most closely related to TLR7 and TLR9 with 43% and 35% overall amino acid sequence identity, respectively and together they constitute one of the six major TLR clades. (1,2)

 

In vivo, TLR8 mRNA is expressed in lung, placenta, spleen, lymph node, bone marrow, and PBLs, with highest expression found in monocytes. In vitro, TLR8 mRNA expression is upregulated in THP-1 cells upon PMA-induced differentiation. TLR8 is highly upregulated by autocrine IL-1β, IL-6, IL-10, and TNF-α, and is even more enhanced by exposure to IFN-γ. TLR8 mRNA expression in THP-1 cells is elevated after exposure to both Gram-positive and Gram-negative bacteria. Ex vivo, monocyte TLR8 expression increases while granulocyte expression decreases on exposure to Gram-negative bacteria. (3) Like TLR7 and TLR7, TLR8 is exclusively localized to intracellular

compartments like endosomes, suggesting that these intracellular TLRs recognize

nucleic acids following the internalization and lysing of viruses.

 

Human TLR8 preferentially mediates the recognition of human immunodeficiency virus, vesicular stomatitis virus, and influenza virus-derived guanosine or uridine rich ss RNA and a synthetic compound (imidazoquinoline compound R848) with antiviral activity R-848. Following nucleic acid recognition, TLR8 recruit the TIR-domain containing adapter called MyD88. MyD88 forms a complex with members of IRAK family (IRAK1 and IRAK4) and TRAF6, which in turn activates TAK1 and results in the activation of NF-κB and synthesis of type I interferons.(4)

 

A novel role for TLR8 as a suppressor of neurite outgrowth as well as an inducer of neuronal apoptosis has been found. Reports suggest that TLR8 functions in neurons through an NF-kappaB-independent mechanism (5).  Recent studies also reveal that the human TLR8 signaling pathway is essential for reversing the function of Treg cells that play a critical role in suppressing immune responses and inducing immune tolerance to cancer and infectious diseases. Thus, the combination of peptide-based vaccines with a TLR8 agonist, may greatly improve the therapeutic potential of cancer vaccines. (4)

 

Reference:

1. Chuang, T.H. & R.J. Ulevitch (2000) Eur. Cytokine Netw. 11:372.

2. Dunne, A. & L.A.J. O’Neill (2003) Sci. STKE 2003:re3.

3. Heine, H. & E. Lein (2003) Int. Arch. Allergy Immunol. 130:180.

4. Oncogene (2008) 27, 190–199; doi:10.1038/sj.onc.1210913

5. Cell Cycle. 2007 Sep;6(23):2859-68. Epub 2007 Sep 4

About Author
IMGENEX India Pvt Ltd. the only biotech company in Orissa and one of its kinds in Eastern India. IMGENEX India started in Oct as an outsourcing branch of IMGENEX Corporation, San Diego, USA. Find out more information about Toll-like receptors .

TLR7- Cluster of Differentiation 287

Toll-like receptor 7 (TLR7), is an immune gene possessed by humans, other mammals and additionally in avian species playing a significant role in initiating antiviral immune responses. It belongs to the evolutionarily conserved Toll-like receptor family. The TLR7 sequence encodes a 1049 amino acid protein with a calculated molecular weight of 121 kDa. Like all other members of the TLR family, TLR7 contain an ectodomain with multiple leucine-rich repeats (LRRs) and a cytoplasmic domain homologous to that of the human interleukin-1 (IL-1) receptor. TLR7 is most closely related to TLR8 and TLR9 with 43% and 36% overall amino acid sequence identity, respectively and thus along with TLR8 and TLR9 constitutes a new sub-family of the TLRs.

 

In vivo, TLR7 mRNA is expressed in lung, placenta, spleen, lymph node, and tonsil. TLR7 mRNA expression is highest in monocytes, B cells, and DC. In vitro, TLR7 mRNA expression is upregulated in THP-1 cells upon PMA-induced differentiation. TLR7 is highly upregulated by exposure to IL-6 and to a slightly lesser extent by autocrine IFN-γ, IL-1β. TLR7 mRNA expression in THP-1 cells is elevated after exposure to both Gram-positive and Gram-negative bacteria. Ex vivo, expression of TLR7 is elevated after exposure to both Gram-positive and Gram-negative bacteria in monocytes and to a greater degree in granulocytes. Like TLR3, it appears that TLR7 may be localized intracellularly (1, 2). In humans, TLR7 is expressed on a restricted range of cell types with the highest abundance found on plasmacytoid dendritic cells and B cells.

 

TLR7 is activated by infections with single-stranded RNA viruses, including influenza virus and vesicular stomatitis virus (VSV). Stimulation of TLR7 with the viral nucleic acids, causes a type I IFN response and secretion of a large quantity of IFNα and the production of inflammatory cytokines [including IFN-alpha, IFN-beta, interleukin-6 (IL-6), IL-12, tumour necrosis factor-alpha (TNF-alpha)]. TLR7 activation also mediates up-regulation of costimulatory molecules (CD40, CD80, CD86), major histocompatibilty complex molecules and chemokine receptors (CCR7) (3). Two signaling pathways of TLR7 are thought to induce inflammatory cytokine expression: the MyD88- IRAK1-TRAF6-IRF5 pathway and the MyD88-TRAF6-TAK1-MAPK/IKK-AP-1/NF-κB pathway.(4) Following nucleic acid recognition, TLR7 recruit the TIR-domain

containing adapter called MyD88. MyD88 forms a complex with members of IRAK family

(IRAK1 and IRAK4) and TRAF6, which in turn activates TAK1 and results in the activation of NF-κB. In addition to single-stranded RNA, the synthetic imidazoquinoline, imiquimod, a low molecular weight immune response modifier, activates TLR7 in both humans and mice, whereas its derivative resiquimod (R-848) activates TLR7 in humans. Both imiquimod and R-848 elicit robust anti-viral and anti-tumor immune responses in vivo, which correlate with a strong induction of type I IFNs. As a consequence of this activity, imiquimod is used for the treatment of external genital warts caused by human Papillomavirus. (5)  TLR7 has been implicated in recognizing guanosine and uracil-rich single-stranded(ss) RNA such as the U5 region of human immunodeficiency virus type 1 RNA and influenza U-rich ssRNA, leading to up-regulation of IFN-alpha.

Reference:

1. Heine, H. & E. Lein (2003) Int. Arch. Allergy Immunol. 130:180.

2. Dunne, A. & L.A.J. O’Neill (2003) Sci. STKE 2003:re3.

3. Victoria J Volume 114 Issue 4 Page 507-521, April 2005

4. Myeong Sup Lee Annual Review of BiochemistryVol. 76: 447-480, 2007.

5. Annett Schoenemeyer J. Biol. Chem., Vol. 280, Issue 17, 17005-17012, April 29, 2005.

About Author
IMGENEX India Pvt Ltd. the only biotech company in Orissa and one of its kinds in Eastern India. IMGENEX India started in Oct as an outsourcing branch of IMGENEX Corporation, San Diego, USA. Find out more information about Toll-like receptors .

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