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{{protein
{{See also|Cell adhesion molecule}}
| Name = intercellular adhesion molecule 1 (CD54)
{{Infobox_gene}}
| caption =  
'''ICAM-1''' ([[Intercellular adhesion molecule|Intercellular Adhesion Molecule]] 1) also known as '''CD54''' ('''C'''luster of '''D'''ifferentiation 54) is a [[protein]] that in humans is encoded by the ''ICAM1'' [[gene]].<ref name="pmid2453850">{{cite journal | vauthors = Carlson M, Nakamura Y, Payson R, O'Connell P, Leppert M, Lathrop GM, Lalouel JM, White R | title = Isolation and mapping of a polymorphic DNA sequence (pMCT108.2) on chromosome 18 [D18S24] | journal = Nucleic Acids Research | volume = 16 | issue = 9 | pages = 4188 | date = May 1988 | pmid = 2453850 | pmc = 336612 | doi = 10.1093/nar/16.9.4188 | url = http://nar.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=2453850 }}</ref><ref name="pmid3871395">{{cite journal | vauthors = Katz FE, Parkar M, Stanley K, Murray LJ, Clark EA, Greaves MF | title = Chromosome mapping of cell membrane antigens expressed on activated B cells | journal = European Journal of Immunology | volume = 15 | issue = 1 | pages = 103–06 | date = Jan 1985 | pmid = 3871395 | doi = 10.1002/eji.1830150121 }}</ref> This gene encodes a cell surface [[glycoprotein]] which is typically expressed on [[endothelium|endothelial]] cells and cells of the [[immune system]]. It binds to [[integrin]]s of type [[CD11a]] / [[CD18]], or [[Integrin alpha M|CD11b]] / CD18 and is also exploited by [[rhinovirus]] as a receptor for entry into [[respiratory epithelium]].<ref name="entrez">{{cite web | title = Entrez Gene: intercellular adhesion molecule 1| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=3383| accessdate = }}</ref>
| image =  
| width =  
| HGNCid = 5344
| Symbol = ICAM1
| AltSymbols =  
| EntrezGene = 3383
| OMIM = 147840
| RefSeq = NM_000201
| UniProt = P05362
| PDB =  
| ECnumber =  
| Chromosome = 19
| Arm = p
| Band = 13.3
| LocusSupplementaryData = -13.2
}}


== Structure ==


==Overview==
ICAM-1 is a member of the [[immunoglobulin superfamily]], the superfamily of proteins including [[antibody|antibodies]] and [[T cell receptor|T-cell receptors]]. ICAM-1 is a transmembrane protein possessing an [[N-terminus|amino-terminus]] extracellular domain, a single transmembrane domain, and a [[C-terminus|carboxy-terminus]] cytoplasmic domain. The structure of ICAM-1 is characterized by heavy [[glycosylation]], and the protein’s extracellular domain is composed of multiple loops created by [[disulfide bridge]]s within the protein. The dominant secondary structure of the protein is the [[beta sheet]], leading researchers to hypothesize the presence of dimerization domains within ICAM-1.<ref name="pmid9539703">{{cite journal | vauthors = Bella J, Kolatkar PR, Marlor CW, Greve JM, Rossmann MG | title = The structure of the two amino-terminal domains of human ICAM-1 suggests how it functions as a rhinovirus receptor and as an LFA-1 integrin ligand | journal = Proceedings |publisher=National Academy of Sciences, USA | volume = 95 | issue = 8 | pages = 4140–45 | date = Apr 1998 | pmid = 9539703 | pmc = 22455 | doi = 10.1073/pnas.95.8.4140 }}</ref>
'''ICAM-1''' is a type of [[intercellular adhesion molecule]] continuously present in low concentrations in the membranes of leukocytes and endothelial cells.  Upon cytokine stimulation, the concentrations greatly increase. ICAM-1 can be induced by [[interleukin-1]] (IL-1) and [[tumor necrosis factor alpha]] (TNFα) and is expressed by the vascular endothelium, [[macrophages]] and [[lymphocytes]].   


ICAM-1 has been implicated in [[subarachnoid hemorrhage]] (SAH).  Levels of ICAM-1 are shown to be significantly elevated in patients with SAH over control subjects in many studies.<ref>Polin RS, Bavbek M, Shaffrey ME, Billups K, Bogaev CA, Kassell NF, Lee KS: Detection of soluble        E-selectin, ICAM-1, VCAM-1 and L-selectin in the cerebrospinal fluid of patients after subarachnoid hemorrhage. '''Journal of Neurosurgery''' 89:559-567,1998.{{Entrez Pubmed|9761049}}</ref> <ref>Frijns CJM, Kappelle LJ: Inflammatory Cell Adhesion Molecules in Ischemic Cerebrovascular Disease. '''Stroke''' 33:2115-2122,2002. {{Entrez Pubmed|12154274}}</ref> While ICAM-1 has not been shown to be directly correlated with cerebral [[vasospasm]], a secondary insult which affects 70% of SAH patients, treatment with anti-ICAM-1 reduced the severity of vasospasm.
== Function ==


==References==
The protein encoded by this gene is a type of [[intercellular adhesion molecule]] continuously present in low concentrations in the membranes of [[leukocytes]] and [[endothelial cells]].  Upon cytokine stimulation, the concentrations greatly increase. ICAM-1 can be induced by [[interleukin-1]] (IL-1) and [[tumor necrosis factor]] (TNF) and is expressed by the vascular endothelium, [[macrophages]], and [[lymphocytes]]. ICAM-1 is a ligand for [[LFA-1]] ([[integrin]]), a receptor found on leukocytes.<ref>{{cite journal | vauthors = Rothlein R, Dustin ML, Marlin SD, Springer TA | title = A human intercellular adhesion molecule (ICAM-1) distinct from LFA-1 | journal = Journal of Immunology | volume = 137 | issue = 4 | pages = 1270–4 | date = August 1986 | pmid = 3525675 }}</ref> When activated, leukocytes bind to endothelial cells via ICAM-1/[[LFA-1]] and then transmigrate into tissues.<ref name="pmid15811956">{{cite journal | vauthors = Yang L, Froio RM, Sciuto TE, Dvorak AM, Alon R, Luscinskas FW | title = ICAM-1 regulates neutrophil adhesion and transcellular migration of TNF-alpha-activated vascular endothelium under flow | journal = Blood | volume = 106 | issue = 2 | pages = 584–92 | date = July 2005 | pmid = 15811956 | pmc = 1635241 | doi = 10.1182/blood-2004-12-4942 }}</ref> LFA-1 has also been found in a soluble form,<ref>{{cite journal | vauthors = Gjelstrup LC, Boesen T, Kragstrup TW, Jørgensen A, Klein NJ, Thiel S, Deleuran BW, Vorup-Jensen T | title = Shedding of large functionally active CD11/CD18 Integrin complexes from leukocyte membranes during synovial inflammation distinguishes three types of arthritis through differential epitope exposure | journal = Journal of Immunology | volume = 185 | issue = 7 | pages = 4154–68 | date = October 2010 | pmid = 20826754 | doi = 10.4049/jimmunol.1000952 }}</ref> which seems to bind and block ICAM-1.<ref>{{cite journal | vauthors = Kragstrup TW, Jalilian B, Hvid M, Kjærgaard A, Østgård R, Schiøttz-Christensen B, Jurik AG, Robinson WH, Vorup-Jensen T, Deleuran B | title = Decreased plasma levels of soluble CD18 link leukocyte infiltration with disease activity in spondyloarthritis | journal = Arthritis Research & Therapy | volume = 16 | issue = 1 | pages = R42 | date = February 2014 | pmid = 24490631 | doi = 10.1186/ar4471 }}</ref>
<references/>


==External links==
=== Role in cell signaling ===
ICAM-1 is an [[endothelium|endothelial]]- and [[leukocyte]]-associated transmembrane protein long known for its importance in stabilizing cell-cell interactions and facilitating leukocyte endothelial transmigration. More recently, ICAM-1 has been characterized as a site for the cellular entry of human [[rhinovirus]].<ref name="pmid6086949">{{cite journal | vauthors = Abraham G, Colonno RJ | title = Many rhinovirus serotypes share the same cellular receptor | journal = Journal of Virology | volume = 51 | issue = 2 | pages = 340–45 | date = Aug 1984 | pmid = 6086949 | pmc = 254443 | doi =  }}</ref> Because of these associations with immune responses, it has been hypothesized that ICAM-1 could function in signal transduction. ICAM-1 ligation produces proinflammatory effects such as inflammatory leukocyte recruitment by signaling through cascades involving a number of kinases, including the kinase [[LYN|p56lyn]].
 
=== Other functions ===
ICAM-1 and [[Soluble cell adhesion molecules|soluble ICAM-1]] have antagonistic effects on the [[tight junction]]s forming the [[blood-testis barrier]], thus playing a major role in [[spermatogenesis]].<ref name=xiao2013>{{cite journal | vauthors = Xiao X, Mruk DD, Cheng CY | title = Intercellular adhesion molecules (ICAMs) and spermatogenesis | journal = Human Reproduction Update | volume = 19 | issue = 2 | pages = 167–86 | year = 2013 | pmid = 23287428 | pmc = 3576004 | doi = 10.1093/humupd/dms049 }}</ref>
 
The presence of heavy glycosylation and other structural characteristics of ICAM-1 lend the protein binding sites for numerous ligands. ICAM-1 possesses binding sites for a number of immune-associated ligands. Notably, ICAM-1 binds to <u>mac</u>rophage adhesion ligand-<u>1</u> (Mac-1; [[CD18|ITGB2]] / [[integrin alpha M|ITGAM]]), <u>l</u>eukocyte <u>f</u>unction associated <u>a</u>ntigen-<u>1</u> ([[CD11a|LFA-1]]), and [[fibrinogen]]. These three proteins are generally expressed on endothelial cells and leukocytes, and they bind to ICAM-1 to facilitate transmigration of leukocytes across vascular endothelia in processes such as extravasation and the inflammatory response. As a result of these binding characteristics, ICAM-1 has classically been assigned the function of intercellular [[cell adhesion|adhesion]].
 
Researchers began to question the role of ICAM-1 as a simple adhesion molecule upon discovering that ICAM-1 serves as the binding site for entry of the major group of human rhinovirus ([[rhinovirus|HRV]]) into various cell types.<ref name="pmid9539703"/> ICAM-1 also became known for its affinity for ''[[plasmodium falciparum]]''-infected erythrocytes (PFIE), providing more of a role for ICAM-1 in infectious disease.
 
With the roles of ICAM-1 in cell-cell adhesion, extravasation, and infection more fully understood, a potential role for ICAM-1 in signal transduction was hypothesized. Most of the work involving ICAM-1 in recent years has focused on this central question as well as related questions. Researchers reasoned that, should ICAM-1 signal transduction prove to occur, it would be necessary to identify the mechanism of that signaling, the conditions and environment in which the signaling would occur, and the biological endpoints of any signaling cascades involved. Beyond its classically described functions as an adhesion and viral entry molecule, ICAM-1 has now been characterized convincingly as possessing a role in signal transduction. Furthermore, the signal-transducing functions of ICAM-1 seem to be associated primarily with proinflammatory pathways. In particular, ICAM-1 signaling seems to produce a recruitment of inflammatory immune cells such as macrophages and granulocytes.<ref name="pmid10395656">{{cite journal | vauthors = Etienne-Manneville S, Chaverot N, Strosberg AD, Couraud PO | title = ICAM-1-coupled signaling pathways in astrocytes converge to cyclic AMP response element-binding protein phosphorylation and TNF-alpha secretion | journal = Journal of Immunology | volume = 163 | issue = 2 | pages = 668–74 | date = Jul 1999 | pmid = 10395656 | doi =  }}</ref>
 
ICAM-1 may also participate in a [[positive feedback]] loop and compete with [[ICAM2|ICAM-2]] to maintain a proinflammatory environment conducive to leukocyte endothelial transmigration. At both the mRNA and protein levels of expression, ICAM-1 ligation was found to upregulate ICAM-1’s own expression in a positive-feedback loop. In addition, the expression of [[CCL5|RANTES]] mRNA and protein was also found to be upregulated by ICAM-1 ligation. RANTES, or Regulated upon Activation Normal T-cell Expressed and Secreted, is a cytokine that is an inflammatory mediator chemotactic for a variety of inflammatory immune cells such as granulocytes and macrophages.<ref name="pmid12506144">{{cite journal | vauthors = Blaber R, Stylianou E, Clayton A, Steadman R | title = Selective regulation of ICAM-1 and RANTES gene expression after ICAM-1 ligation on human renal fibroblasts | journal = Journal of the American Society of Nephrology | volume = 14 | issue = 1 | pages = 116–27 | date = Jan 2003 | pmid = 12506144 | doi = 10.1097/01.ASN.0000040595.35207.62 }}</ref> However, much work remains to be done in fully characterizing the signaling of ICAM-1. The relationship between ICAM-1 and ICAM-2 signaling environments has not been established beyond mere correlation; a study linking ICAM signaling to actual modulation of an inflammatory environment in vivo has yet to be conducted. The reticular nature of signaling cascades necessitates that the downstream effectors of ICAM-1 mediated signaling through various kinases including [[LYN|p56lyn]], [[c-Raf|Raf-1]], and the [[mitogen-activated protein kinase|MAPKs]] are largely unknown. A more thorough study of the cross-talk between these signaling molecules may shed further light onto the biological endpoints produced by ICAM-1 ligation and signal transduction.
 
== Clinical significance ==
 
ICAM-1 has been implicated in [[subarachnoid hemorrhage]] (SAH).  Levels of ICAM-1 are shown to be significantly elevated in patients with SAH over control subjects in many studies.<ref name="pmid9761049">{{cite journal | vauthors = Polin RS, Bavbek M, Shaffrey ME, Billups K, Bogaev CA, Kassell NF, Lee KS | title = Detection of soluble E-selectin, ICAM-1, VCAM-1, and L-selectin in the cerebrospinal fluid of patients after subarachnoid hemorrhage | journal = Journal of Neurosurgery | volume = 89 | issue = 4 | pages = 559–67 | date = Oct 1998 | pmid = 9761049 | doi = 10.3171/jns.1998.89.4.0559 }}</ref><ref name="pmid12154274">{{cite journal | vauthors = Frijns CJ, Kappelle LJ | title = Inflammatory cell adhesion molecules in ischemic cerebrovascular disease | journal = Stroke: A Journal of Cerebral Circulation | volume = 33 | issue = 8 | pages = 2115–22 | date = Aug 2002 | pmid = 12154274 | doi = 10.1161/01.STR.0000021902.33129.69 | url = http://stroke.ahajournals.org/cgi/pmidlookup?view=long&pmid=12154274 }}</ref> While ICAM-1 has not been shown to be directly correlated with cerebral [[vasospasm]], a secondary symptom that affects 70% of SAH patients, treatment with anti-ICAM-1 reduced the severity of vasospasm.
 
ICAM-1 expressed by [[respiratory epithelial cell]]s is also the binding site for [[rhinovirus]], the causative agent of most [[common cold]]s.
 
ICAM-1 has an important role in ocular allergies recruiting pro-inflammatory lymphocytes and mast cells promoting a [[type I hypersensitivity]] reaction.
 
[[Cannabinoid]] [[Cannabinoid receptor type 2|CB2]] [[Cannabinoid receptor|receptor]] [[Agonist|agonists]] is found to decrease the induction of ICAM-1 and [[VCAM-1]] surface expression in human [[Human brain|brain tissues]] and primary human brain [[endothelial cells]] (BMVEC) exposed to various pro-inflammatory mediators.<ref>{{cite journal | vauthors = Ramirez SH, Haskó J, Skuba A, Fan S, Dykstra H, McCormick R, Reichenbach N, Krizbai I, Mahadevan A, Zhang M, Tuma R, Son YJ, Persidsky Y | title = Activation of cannabinoid receptor 2 attenuates leukocyte-endothelial cell interactions and blood-brain barrier dysfunction under inflammatory conditions | journal = The Journal of Neuroscience | volume = 32 | issue = 12 | pages = 4004–16 | date = March 2012 | pmid = 22442067 | pmc = 3325902 | doi = 10.1523/JNEUROSCI.4628-11.2012 }}</ref>
 
== Interactions ==
 
ICAM-1 has been shown to [[Protein-protein interaction|interact]] with [[CD11a]],<ref name=pmid11279101>{{cite journal | vauthors = Lu C, Takagi J, Springer TA | title = Association of the membrane proximal regions of the alpha and beta subunit cytoplasmic domains constrains an integrin in the inactive state | journal = The Journal of Biological Chemistry | volume = 276 | issue = 18 | pages = 14642–48 | date = May 2001 | pmid = 11279101 | doi = 10.1074/jbc.M100600200 | authorlink2 = Springer T A }}</ref><ref name=pmid12526797>{{cite journal | vauthors = Shimaoka M, Xiao T, Liu JH, Yang Y, Dong Y, Jun CD, McCormack A, Zhang R, Joachimiak A, Takagi J, Wang JH, Springer TA | title = Structures of the alpha L I domain and its complex with ICAM-1 reveal a shape-shifting pathway for integrin regulation | journal = Cell | volume = 112 | issue = 1 | pages = 99–111 | date = Jan 2003 | pmid = 12526797 | doi = 10.1016/S0092-8674(02)01257-6 | authorlink2 = Springer Timothy A }}</ref><ref name=pmid11786177>{{cite journal | vauthors = Yusuf-Makagiansar H, Makagiansar IT, Hu Y, Siahaan TJ | title = Synergistic inhibitory activity of alpha- and beta-LFA-1 peptides on LFA-1/ICAM-1 interaction | journal = Peptides | volume = 22 | issue = 12 | pages = 1955–62 | date = Dec 2001 | pmid = 11786177 | doi = 10.1016/S0196-9781(01)00546-0 }}</ref> [[ezrin|EZR]]<ref name=pmid9705328>{{cite journal | vauthors = Heiska L, Alfthan K, Grönholm M, Vilja P, Vaheri A, Carpén O | title = Association of ezrin with intercellular adhesion molecule-1 and -2 (ICAM-1 and ICAM-2). Regulation by phosphatidylinositol 4, 5-bisphosphate | journal = The Journal of Biological Chemistry | volume = 273 | issue = 34 | pages = 21893–900 | date = Aug 1998 | pmid = 9705328 | doi = 10.1074/jbc.273.34.21893 }}</ref> and [[CD18]].<ref name=pmid11279101/><ref name=pmid10352278>{{cite journal | vauthors = Kotovuori A, Pessa-Morikawa T, Kotovuori P, Nortamo P, Gahmberg CG | title = ICAM-2 and a peptide from its binding domain are efficient activators of leukocyte adhesion and integrin affinity | journal = Journal of Immunology | volume = 162 | issue = 11 | pages = 6613–20 | date = Jun 1999 | pmid = 10352278 }}</ref><ref name=pmid7642561>{{cite journal | vauthors = Huang C, Springer TA | title = A binding interface on the I domain of lymphocyte function-associated antigen-1 (LFA-1) required for specific interaction with intercellular adhesion molecule 1 (ICAM-1) | journal = The Journal of Biological Chemistry | volume = 270 | issue = 32 | pages = 19008–16 | date = Aug 1995 | pmid = 7642561 | doi = 10.1074/jbc.270.32.19008 | authorlink2 = Springer T A }}</ref>
 
== References ==
{{Reflist}}
 
== Further reading ==
{{Refbegin|33em}}
* {{cite journal | vauthors = Wahl SM, Greenwell-Wild T, Hale-Donze H, Moutsopoulos N, Orenstein JM | title = Permissive factors for HIV-1 infection of macrophages | journal = Journal of Leukocyte Biology | volume = 68 | issue = 3 | pages = 303–10 | date = Sep 2000 | pmid = 10985244 | doi =  | displayauthors = 1 }}
* {{cite journal | vauthors = Yonekawa K, Harlan JM | title = Targeting leukocyte integrins in human diseases | journal = Journal of Leukocyte Biology | volume = 77 | issue = 2 | pages = 129–40 | date = Feb 2005 | pmid = 15548573 | doi = 10.1189/jlb.0804460 }}
* {{cite journal | vauthors = Chakravorty SJ, Craig A | title = The role of ICAM-1 in Plasmodium falciparum cytoadherence | journal = European Journal of Cell Biology | volume = 84 | issue = 1 | pages = 15–27 | date = Jan 2005 | pmid = 15724813 | doi = 10.1016/j.ejcb.2004.09.002 }}
* {{cite journal | vauthors = Lebedeva T, Dustin ML, Sykulev Y | title = ICAM-1 co-stimulates target cells to facilitate antigen presentation | journal = Current Opinion in Immunology | volume = 17 | issue = 3 | pages = 251–58 | date = Jun 2005 | pmid = 15886114 | doi = 10.1016/j.coi.2005.04.008 }}
* {{cite journal | vauthors = Yang L, Froio RM, Sciuto TE, Dvorak AM, Alon R, Luscinskas FW | title = ICAM-1 regulates neutrophil adhesion and transcellular migration of TNF-alpha-activated vascular endothelium under flow | journal = Blood | volume = 106 | issue = 2 | pages = 584–92 | date = Jul 2005 | pmid = 15811956 | pmc = 1635241 | doi = 10.1182/blood-2004-12-4942 }}
{{Refend}}
 
== External links ==
* {{MeshName|Intercellular+Adhesion+Molecule-1}}
* {{MeshName|Intercellular+Adhesion+Molecule-1}}


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Latest revision as of 15:01, 12 September 2018

See also: Cell adhesion molecule
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ICAM-1 (Intercellular Adhesion Molecule 1) also known as CD54 (Cluster of Differentiation 54) is a protein that in humans is encoded by the ICAM1 gene.[1][2] This gene encodes a cell surface glycoprotein which is typically expressed on endothelial cells and cells of the immune system. It binds to integrins of type CD11a / CD18, or CD11b / CD18 and is also exploited by rhinovirus as a receptor for entry into respiratory epithelium.[3]

Structure

ICAM-1 is a member of the immunoglobulin superfamily, the superfamily of proteins including antibodies and T-cell receptors. ICAM-1 is a transmembrane protein possessing an amino-terminus extracellular domain, a single transmembrane domain, and a carboxy-terminus cytoplasmic domain. The structure of ICAM-1 is characterized by heavy glycosylation, and the protein’s extracellular domain is composed of multiple loops created by disulfide bridges within the protein. The dominant secondary structure of the protein is the beta sheet, leading researchers to hypothesize the presence of dimerization domains within ICAM-1.[4]

Function

The protein encoded by this gene is a type of intercellular adhesion molecule continuously present in low concentrations in the membranes of leukocytes and endothelial cells. Upon cytokine stimulation, the concentrations greatly increase. ICAM-1 can be induced by interleukin-1 (IL-1) and tumor necrosis factor (TNF) and is expressed by the vascular endothelium, macrophages, and lymphocytes. ICAM-1 is a ligand for LFA-1 (integrin), a receptor found on leukocytes.[5] When activated, leukocytes bind to endothelial cells via ICAM-1/LFA-1 and then transmigrate into tissues.[6] LFA-1 has also been found in a soluble form,[7] which seems to bind and block ICAM-1.[8]

Role in cell signaling

ICAM-1 is an endothelial- and leukocyte-associated transmembrane protein long known for its importance in stabilizing cell-cell interactions and facilitating leukocyte endothelial transmigration. More recently, ICAM-1 has been characterized as a site for the cellular entry of human rhinovirus.[9] Because of these associations with immune responses, it has been hypothesized that ICAM-1 could function in signal transduction. ICAM-1 ligation produces proinflammatory effects such as inflammatory leukocyte recruitment by signaling through cascades involving a number of kinases, including the kinase p56lyn.

Other functions

ICAM-1 and soluble ICAM-1 have antagonistic effects on the tight junctions forming the blood-testis barrier, thus playing a major role in spermatogenesis.[10]

The presence of heavy glycosylation and other structural characteristics of ICAM-1 lend the protein binding sites for numerous ligands. ICAM-1 possesses binding sites for a number of immune-associated ligands. Notably, ICAM-1 binds to macrophage adhesion ligand-1 (Mac-1; ITGB2 / ITGAM), leukocyte function associated antigen-1 (LFA-1), and fibrinogen. These three proteins are generally expressed on endothelial cells and leukocytes, and they bind to ICAM-1 to facilitate transmigration of leukocytes across vascular endothelia in processes such as extravasation and the inflammatory response. As a result of these binding characteristics, ICAM-1 has classically been assigned the function of intercellular adhesion.

Researchers began to question the role of ICAM-1 as a simple adhesion molecule upon discovering that ICAM-1 serves as the binding site for entry of the major group of human rhinovirus (HRV) into various cell types.[4] ICAM-1 also became known for its affinity for plasmodium falciparum-infected erythrocytes (PFIE), providing more of a role for ICAM-1 in infectious disease.

With the roles of ICAM-1 in cell-cell adhesion, extravasation, and infection more fully understood, a potential role for ICAM-1 in signal transduction was hypothesized. Most of the work involving ICAM-1 in recent years has focused on this central question as well as related questions. Researchers reasoned that, should ICAM-1 signal transduction prove to occur, it would be necessary to identify the mechanism of that signaling, the conditions and environment in which the signaling would occur, and the biological endpoints of any signaling cascades involved. Beyond its classically described functions as an adhesion and viral entry molecule, ICAM-1 has now been characterized convincingly as possessing a role in signal transduction. Furthermore, the signal-transducing functions of ICAM-1 seem to be associated primarily with proinflammatory pathways. In particular, ICAM-1 signaling seems to produce a recruitment of inflammatory immune cells such as macrophages and granulocytes.[11]

ICAM-1 may also participate in a positive feedback loop and compete with ICAM-2 to maintain a proinflammatory environment conducive to leukocyte endothelial transmigration. At both the mRNA and protein levels of expression, ICAM-1 ligation was found to upregulate ICAM-1’s own expression in a positive-feedback loop. In addition, the expression of RANTES mRNA and protein was also found to be upregulated by ICAM-1 ligation. RANTES, or Regulated upon Activation Normal T-cell Expressed and Secreted, is a cytokine that is an inflammatory mediator chemotactic for a variety of inflammatory immune cells such as granulocytes and macrophages.[12] However, much work remains to be done in fully characterizing the signaling of ICAM-1. The relationship between ICAM-1 and ICAM-2 signaling environments has not been established beyond mere correlation; a study linking ICAM signaling to actual modulation of an inflammatory environment in vivo has yet to be conducted. The reticular nature of signaling cascades necessitates that the downstream effectors of ICAM-1 mediated signaling through various kinases including p56lyn, Raf-1, and the MAPKs are largely unknown. A more thorough study of the cross-talk between these signaling molecules may shed further light onto the biological endpoints produced by ICAM-1 ligation and signal transduction.

Clinical significance

ICAM-1 has been implicated in subarachnoid hemorrhage (SAH). Levels of ICAM-1 are shown to be significantly elevated in patients with SAH over control subjects in many studies.[13][14] While ICAM-1 has not been shown to be directly correlated with cerebral vasospasm, a secondary symptom that affects 70% of SAH patients, treatment with anti-ICAM-1 reduced the severity of vasospasm.

ICAM-1 expressed by respiratory epithelial cells is also the binding site for rhinovirus, the causative agent of most common colds.

ICAM-1 has an important role in ocular allergies recruiting pro-inflammatory lymphocytes and mast cells promoting a type I hypersensitivity reaction.

Cannabinoid CB2 receptor agonists is found to decrease the induction of ICAM-1 and VCAM-1 surface expression in human brain tissues and primary human brain endothelial cells (BMVEC) exposed to various pro-inflammatory mediators.[15]

Interactions

ICAM-1 has been shown to interact with CD11a,[16][17][18] EZR[19] and CD18.[16][20][21]

References

  1. ↑ Carlson M, Nakamura Y, Payson R, O'Connell P, Leppert M, Lathrop GM, Lalouel JM, White R (May 1988). "Isolation and mapping of a polymorphic DNA sequence (pMCT108.2) on chromosome 18 [D18S24]". Nucleic Acids Research. 16 (9): 4188. doi:10.1093/nar/16.9.4188. PMC 336612. PMID 2453850.
  2. ↑ Katz FE, Parkar M, Stanley K, Murray LJ, Clark EA, Greaves MF (Jan 1985). "Chromosome mapping of cell membrane antigens expressed on activated B cells". European Journal of Immunology. 15 (1): 103–06. doi:10.1002/eji.1830150121. PMID 3871395.
  3. ↑ "Entrez Gene: intercellular adhesion molecule 1".
  4. ↑ 4.0 4.1 Bella J, Kolatkar PR, Marlor CW, Greve JM, Rossmann MG (Apr 1998). "The structure of the two amino-terminal domains of human ICAM-1 suggests how it functions as a rhinovirus receptor and as an LFA-1 integrin ligand". Proceedings. National Academy of Sciences, USA. 95 (8): 4140–45. doi:10.1073/pnas.95.8.4140. PMC 22455. PMID 9539703.
  5. ↑ Rothlein R, Dustin ML, Marlin SD, Springer TA (August 1986). "A human intercellular adhesion molecule (ICAM-1) distinct from LFA-1". Journal of Immunology. 137 (4): 1270–4. PMID 3525675.
  6. ↑ Yang L, Froio RM, Sciuto TE, Dvorak AM, Alon R, Luscinskas FW (July 2005). "ICAM-1 regulates neutrophil adhesion and transcellular migration of TNF-alpha-activated vascular endothelium under flow". Blood. 106 (2): 584–92. doi:10.1182/blood-2004-12-4942. PMC 1635241. PMID 15811956.
  7. ↑ Gjelstrup LC, Boesen T, Kragstrup TW, Jørgensen A, Klein NJ, Thiel S, Deleuran BW, Vorup-Jensen T (October 2010). "Shedding of large functionally active CD11/CD18 Integrin complexes from leukocyte membranes during synovial inflammation distinguishes three types of arthritis through differential epitope exposure". Journal of Immunology. 185 (7): 4154–68. doi:10.4049/jimmunol.1000952. PMID 20826754.
  8. ↑ Kragstrup TW, Jalilian B, Hvid M, Kjærgaard A, Østgård R, Schiøttz-Christensen B, Jurik AG, Robinson WH, Vorup-Jensen T, Deleuran B (February 2014). "Decreased plasma levels of soluble CD18 link leukocyte infiltration with disease activity in spondyloarthritis". Arthritis Research & Therapy. 16 (1): R42. doi:10.1186/ar4471. PMID 24490631.
  9. ↑ Abraham G, Colonno RJ (Aug 1984). "Many rhinovirus serotypes share the same cellular receptor". Journal of Virology. 51 (2): 340–45. PMC 254443. PMID 6086949.
  10. ↑ Xiao X, Mruk DD, Cheng CY (2013). "Intercellular adhesion molecules (ICAMs) and spermatogenesis". Human Reproduction Update. 19 (2): 167–86. doi:10.1093/humupd/dms049. PMC 3576004. PMID 23287428.
  11. ↑ Etienne-Manneville S, Chaverot N, Strosberg AD, Couraud PO (Jul 1999). "ICAM-1-coupled signaling pathways in astrocytes converge to cyclic AMP response element-binding protein phosphorylation and TNF-alpha secretion". Journal of Immunology. 163 (2): 668–74. PMID 10395656.
  12. ↑ Blaber R, Stylianou E, Clayton A, Steadman R (Jan 2003). "Selective regulation of ICAM-1 and RANTES gene expression after ICAM-1 ligation on human renal fibroblasts". Journal of the American Society of Nephrology. 14 (1): 116–27. doi:10.1097/01.ASN.0000040595.35207.62. PMID 12506144.
  13. ↑ Polin RS, Bavbek M, Shaffrey ME, Billups K, Bogaev CA, Kassell NF, Lee KS (Oct 1998). "Detection of soluble E-selectin, ICAM-1, VCAM-1, and L-selectin in the cerebrospinal fluid of patients after subarachnoid hemorrhage". Journal of Neurosurgery. 89 (4): 559–67. doi:10.3171/jns.1998.89.4.0559. PMID 9761049.
  14. ↑ Frijns CJ, Kappelle LJ (Aug 2002). "Inflammatory cell adhesion molecules in ischemic cerebrovascular disease". Stroke: A Journal of Cerebral Circulation. 33 (8): 2115–22. doi:10.1161/01.STR.0000021902.33129.69. PMID 12154274.
  15. ↑ Ramirez SH, Haskó J, Skuba A, Fan S, Dykstra H, McCormick R, Reichenbach N, Krizbai I, Mahadevan A, Zhang M, Tuma R, Son YJ, Persidsky Y (March 2012). "Activation of cannabinoid receptor 2 attenuates leukocyte-endothelial cell interactions and blood-brain barrier dysfunction under inflammatory conditions". The Journal of Neuroscience. 32 (12): 4004–16. doi:10.1523/JNEUROSCI.4628-11.2012. PMC 3325902. PMID 22442067.
  16. ↑ 16.0 16.1 Lu C, Takagi J, Springer TA (May 2001). "Association of the membrane proximal regions of the alpha and beta subunit cytoplasmic domains constrains an integrin in the inactive state". The Journal of Biological Chemistry. 276 (18): 14642–48. doi:10.1074/jbc.M100600200. PMID 11279101.
  17. ↑ Shimaoka M, Xiao T, Liu JH, Yang Y, Dong Y, Jun CD, McCormack A, Zhang R, Joachimiak A, Takagi J, Wang JH, Springer TA (Jan 2003). "Structures of the alpha L I domain and its complex with ICAM-1 reveal a shape-shifting pathway for integrin regulation". Cell. 112 (1): 99–111. doi:10.1016/S0092-8674(02)01257-6. PMID 12526797.
  18. ↑ Yusuf-Makagiansar H, Makagiansar IT, Hu Y, Siahaan TJ (Dec 2001). "Synergistic inhibitory activity of alpha- and beta-LFA-1 peptides on LFA-1/ICAM-1 interaction". Peptides. 22 (12): 1955–62. doi:10.1016/S0196-9781(01)00546-0. PMID 11786177.
  19. ↑ Heiska L, Alfthan K, Grönholm M, Vilja P, Vaheri A, Carpén O (Aug 1998). "Association of ezrin with intercellular adhesion molecule-1 and -2 (ICAM-1 and ICAM-2). Regulation by phosphatidylinositol 4, 5-bisphosphate". The Journal of Biological Chemistry. 273 (34): 21893–900. doi:10.1074/jbc.273.34.21893. PMID 9705328.
  20. ↑ Kotovuori A, Pessa-Morikawa T, Kotovuori P, Nortamo P, Gahmberg CG (Jun 1999). "ICAM-2 and a peptide from its binding domain are efficient activators of leukocyte adhesion and integrin affinity". Journal of Immunology. 162 (11): 6613–20. PMID 10352278.
  21. ↑ Huang C, Springer TA (Aug 1995). "A binding interface on the I domain of lymphocyte function-associated antigen-1 (LFA-1) required for specific interaction with intercellular adhesion molecule 1 (ICAM-1)". The Journal of Biological Chemistry. 270 (32): 19008–16. doi:10.1074/jbc.270.32.19008. PMID 7642561.

Further reading

External links

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