tsp-1 is the best - studied member of the thrombospondin ( tsp ) family , which consists of five extracellular calcium - binding multifunctional proteins : tsp-1 , tsp-2 , tsp-3 , tsp-4 , and tsp-5 . tsp-1 and tsp-2 are structurally similar , and they are expressed on the cell surface during physiological events . a variety of normal cells , including endothelial cells , fibroblasts , adipocytes , smooth muscle cells , monocytes , macrophages , and transformed cells such as malignant glioma cells , secrete tsp-1 [ 2 , 3 ] .   
tsp-1 binds to protein components of the extracellular matrix , such as fibronectin . by this way ,
tsp-1-specific domains bind to proteoglycans , membrane proteins such as integrins , and other matrix proteins expressed by a variety of cells [ 4 , 5 ] .  
tsp-1 contains an n - terminal globular domain that binds heparin , the type i , type ii , and type iii repeats , and a terminal globular domain .
the nh2-terminal , heparin - binding domain of tsp-1 interacts with low - density lipoprotein receptor - related protein ( lrp1 ) .
this tsp-1 domain also binds heparin sulfate proteoglycans and a number of integrins that have an important function in angiogenesis , chemotaxis adhesion , and cell motility .
all five members of the tsp family have the repeat domains type ii and iii , but only tsp-1 and tsp-2 contain the type i repeats .
type i repeats , also called thrombospondin structural homology repeats ( tsrs ) , inhibit angiogenesis by activating cd36 and inducing apoptosis in endothelial cells .
cd36 ( also known as fatty acid translocase , fat ) is a glycosylated protein member of the class b scavenger receptor family .
it plays an important role in multiple processes such as fatty acid and glucose metabolism .
cd36 is found on the surface of diverse cell types and binds to many ligands , including tsp-1 [ 10 , 11 ] .
it has been reported that upon binding with tsp-1 , cd36 dimerizes , becoming actively involved in signal transduction . however , activation of cd36 as a monomer has also been reported .
the adhesive and antiangiogenic functions of tsp-1 have been mainly attributed to its interaction with cd36 .
other domains of tsp-1 can , however , impact these functions by interacting with other key receptors as it will be discussed in succeeding sections .
tgf1 mediates wound healing , cell proliferation , extracellular matrix formation , and the immune response .
this multifunctional cytokine is secreted to the extracellular matrix in its inactive form , by virtue of its noncovalent association with the latency - associated peptide ( lap ) .
the activating function of tsp-1 is due to the amino acid sequence rfk located in the tsr [ 1416 ] .
tsp-1 releases tgf1 from its latent form when it interacts with the n - terminal region of lap and binds the mature tgf1 .
this interaction results in the formation of a complex that involves conformational changes in tgf1 ,   making it accessible to its receptor .
lap is crucial for tgf1 activation and regulates many of its functions ; additionally , lap has functions in inflammation independently of tgf1 , such as the induction of chemotaxis of monocytes to injured tissues .  
they contain amino acid sequences that interact with the neutrophil elastase , and upon this binding these repeats activate neutrophils [ 18 , 19 ] .
these type 3 repeats also inhibit the binding of fibroblast growth factor to endothelial cells , reducing angiogenesis .
the cooh - terminal domain of tsp-1 binds to cd47 , also known as integrin - associated protein .  
this domain also interacts with integrins such as 1 and v6 integrins and actively binds to proteoglycans allowing cell adhesion and spreading . these and other interactions significantly affect angiogenesis , cell proliferation , and immune responses . tsp-1
binding with cd47 also regulates nitric oxide ( no ) , a biogas , quite important in both normal and pathological events . by modulating the effects of no , the carboxy - terminal domain of tsp-1 has important function in vasodilation and chemotaxis .
this receptor inhibits no as well as all its vascular functions even when tsp-1 is present at very low ( physiological ) concentrations .
analysis of wound bed vascularity at 72 hours after skin grafting from tsp-1 and cd47 null mice shows significant increased numbers of blood vessels .
most recently it has been reported that cd47 associates with the receptor of vascular endothelial growth factor , vegfr2 .
however , the binding of cd47 with tsp1 or other ligands inhibits vegfr2 phosphorylation and further angiogenesis .
this paper focuses on well - known interactions of tsp-1 with key receptors and growth factors during the initial inflammatory events throughout the chronic inflammatory processes .
new developments are also herein discussed , showing the involvement of tsp-1 in pivotal transcriptional pathways related to inflammation and inflammation - induced carcinogenesis .
the inflammatory acute process begins when cells sense the injury , and they release chemical mediators called cytokines .
local macrophages express surface membrane receptors called toll - like receptors ( tlr ) that recognize specific types of antigens .
once activated , tlr triggers the release of more cytokines promoting inflammation and attracting white blood cells .
cytokines will promote leukocytosis by inducing factors favoring the rapid release of neutrophils from the red bone marrow .
neutrophils enter the blood stream , and by diapedesis they emigrate outside the blood vessels .
chemotactic agents accelerate the migration of leukocytes to the site of injury such as monocytes , which later become macrophages , engulfing any on - site cell debris or pathogens .
in addition , mast cells ( producing histamine ) , injured tissue cells , phagocytes , lymphocytes , basophils , and blood proteins are all sources of inflammatory mediators .  
tsp-1 is transiently released early during the acute phase of inflammation , and multiple factors seem to modulate the release of tsp-1 during this process .
tsp-1 is strongly expressed in neutrophils , inducing an intense chemotactic response to injured tissues .
tsp-1 is secreted in response to inflammation , promoting the resolution of the inflammatory process and facilitating phagocytosis of damaged cells [ 25 , 26 ] .
thus , enhanced production of tsp-1 could be a compensatory mechanism for controlling the immune response and protecting tissues from excessive damage .  
this receptor is coexpressed with tsp-1 in macrophages and endothelial cells , and , by binding with cd36 ( figure 2 ) , tsp-1 induces apoptosis in endothelial cells . by activating cd36
, tsp-1 also controls blood flow and leukocyte infiltration modulating the action of the no pathway in injured tissues .
no is a gas produced when l - arginine is converted to l - citruline by the enzyme nitric oxide synthase ( nos )
. there are four different isoforms of nos , neuronal ( nnos ) , endothelial ( enos ) , mitochondrial ( mtnos ) , and the inducible isoform ( inos ) .
the first two are secreted during normal physiological events , but only inos is expressed upon inflammatory stimuli .
the effects of no in inflammation have been extensively recognized in a variety of studies .
no can modulate leukocyte adhesion in a dose - dependent manner . at low doses ,
no is anti - inflammatory and antiangiogenic but , after inflammatory stimuli , high levels of no are secreted promoting angiogenesis and leukocyte adhesion to the endothelium .
tsp-1 could inhibit the soluble guanylyl cyclase system in endothelial cells and consequently the activation of no by interacting with cd36 and cd47 . through this mechanism
, tsp-1 inhibits inflammation by blocking adhesion and activation of leukocytes to the endothelium and diminishing angiogenesis [ 22 , 30 , 31 ] .  
another factor interacting with tsp-1 during early inflammation is the peroxisome proliferator - activated receptor ( ppar ) .
ppar greatly enhances the proapoptotic effects of the tsp-1-derived peptide abt510 ( abbott laboratories ) [ 33 , 34 ] .
this peptide corresponds to the tsr of tsp-1 and induces vascular apoptosis in vitro and in vivo through its interaction with cd36 . by using a ppar agonist , the expression of cd36 in endothelial cells
the tsp-1 receptor cd47 is critical for the migration of leukocytes through endothelial and epithelial barriers .
cd47 is strongly expressed in polymorphonuclear cells , and its activation enhances the expression of tsp-1 in leukocytes .
cd47 can directly cause apoptosis through mitochondrial mechanisms , or by activation of the fas / cd95 pathway .
expression of cd47 in apoptotic granulocytes can influence the phagocytic functions of the macrophages in inflammatory sites suggesting a critical role of this factor in the resolution of the process   ( figure 2 ) .
acute inflammation could advance to a resolution , progress to the formation of an abscess , walling off by fibrotic capsule , or evolve as scar upon tissue destruction , fibrin and collagen deposition .
chronic inflammation is characterized by infiltration of mononuclear cells , macrophages , lymphocytes , and plasma cells .
chronically inflamed tissues have fibroblast proliferation , angiogenesis , tissue destruction , and fibrosis .  
they invade the injured area during the acute process but , if the cause is not eliminated , infiltration by macrophages persists for long periods of time .
the continued secretion of chemotactic factors allows the constant supply of monocytes from the blood and their conversion to macrophages .
these cells are key for further lymphocyte infiltration , fibroblast proliferation , tissue destruction , and fibrosis .
lymphocytes arise from the hemoblasts of the bone marrow , and later they develop immunocompentence and self - tolerance .
plasma cells or b lymphocytes produce antibodies against antigens persisting in the area and therefore provide humoral immunity .
included in this group are dendritic cells ( dcs ) , which internalize antigens and present antigenic determinants on their surface for recognition by t lymphocytes .
they are part of the adaptive immune system that recognizes something as foreign and acts to immobilize and remove it . during the early stages of injury and inflammation , high levels of
tsp-1 can modulate inflammation by inhibiting or enhancing the secretion of the cytokine interleukin 10 ( il10 ) , by this way , tsp-1 can also regulate the functions of dc .
in addition , after adding il-6 , il-10 , or tgf1 to cultured dc , they become immune tolerant and show upregulation of intracellular tsp-1 .
tsp-1 also inhibits the function of apc by suppressing their capacity to sensitize t - cells in the host .
this is demonstrated in a corneal transplantation model , in which most of the corneal tsp-1 null allografts are rejected   .
cd47 has also a crucial role in t - cell activation [ 42 , 43 ] .
interaction of tsp-1 with cd47 promotes the activation of thymus - derived cd4 + cd25 + t regulatory cells ( tregs ) . through this mechanism
suppression of cd47 or tsp-1 expression in dc by using small interfering rna ( sirna ) technique actually protects newborn mice against bacterial ( escherichia coli ) meningitis .
again , the loss of cd47 activity prevents the maturation of the dcs and the production of inflammatory cytokines . in conclusion
, cd47 seems to have pivotal functions in inflammation and provides a major mechanistic pathway for the functions of tsp-1 in that process .  
cd36 mice exhibit an impaired early proinflammatory response to infection , elevation of cytokines , and higher mortality [ 45 , 46 ] .
these findings suggest that cd36 is quite critical for the recognition and clearance of pathogens in acute and chronic infections . by binding to this receptor
, tsp-1 could modulate the inflammatory process by activating macrophages and favoring phagocytosis . during chronic inflammation ,
these adaptive immune mechanisms provide defense against disease and are regulated by cellular interactions and cytokines .  
b lymphocytes secrete antibodies that bind to infectious agents and label them for destruction or elimination .
once inside a cell , a pathogen becomes inaccessible to those antibodies and cytotoxic t cells could destroy them by inducing apoptosis of the cell host .
regulatory t cells can modulate the secretion of cytokines enhancing the functions of macrophages and b - lymphocytes .
tsp-1 has been reported to decrease immune responses by inhibition of t - cell effectors , or by directly inducing t cell apoptosis [ 47 , 48 ] .
in addition , by binding to 41 integrin tsp-1 promotes t - cell adhesion and chemotaxis .  
tgf1 activation is a crucial element in intestinal homeostasis . in the intestinal tract , an abnormal response to
the normal gut flora is a characteristic of the pathogenesis of inflammatory bowel disease ( ibd ) .
mucosal t cells from patients with ibd express high levels of smad7 , an inhibitor of tgf1 signaling . by this mechanism , tgf1 mediates intestinal healing and susceptibility to injury [ 5053 ] .
however , by activating tgf1 , tsp-1 also enhances fibrosis and compromises organ function [ 54 , 55 ] ( figure 3 ) . during the immune response , leukocytes produce reactive oxygen species ( ros ) that include free radicals and peroxides .
ros are quite important for the killing of pathogens , but they can also produce cell damage .
tgf1 favors the formation of ros , and , as a cycle , ros can also activate tgf1 promoting apoptosis and fibrosis .  
angiogenesis is an active component of chronic inflammatory diseases such as rheumatoid arthritis , atherosclerosis , diabetic retinopathy , airway inflammation , and others .
tsp-1 exerts a powerful antiangiogenic effect , and this function has a significant impact in chronic inflammation .
activated endothelial cells secrete cytokines , chemokines , matrix metalloproteinases , and growth factors that can greatly influence the inflammatory reaction and promote carcinogenesis .
tsp-1 deficient mice display extensive acute pneumonia , leukocytosis , pancreatitis , and inflammatory infiltrates in the lacrimal glands [ 26 , 58 , 59 ] .
this phenotype suggests that tsp-1 has a significant role in inflammation , a role that has not been exhaustively analyzed .
tsp-1 has anti - inflammatory and proinflammatory effects observed in several diseases and animal models .
these contrasting functions in inflammation are possible due to interactions with multiple receptors or to the presence of specific matricellular proteins in injured tissue .
in addition , tsp-1 might act by a biphasic or dose - dependent mechanism .  
tsp-1 enhances fibrosis and renal damage by its interaction with tgf1 , while lskl , a peptide antagonist of tsp-1 , reduces renal interstitial fibrosis in a rat experimental model of kidney disease .
this effect is attributed to the competitive properties of lskl that prevents tsp-1-mediated activation of tgf1 .  
tsp-1 is also expressed in glomerulopathies and is considered an early marker of inflammation and fibrosis .
the development of diabetic nephropathy is attenuated in tsp-1-deficient mice as demonstrated by a significant reduction of glomerulosclerosis , glomerular matrix accumulation , podocyte injury , renal infiltration with inflammatory cells , and alterations of renal functional parameters .   as an activator of tgf1
, tsp-1 could modulate the functions of tgf1 in cardiovascular diseases , atherosclerosis , and obesity .
inflammatory cells secrete tsp-1 during the acute phase of the healing process in myocardial infarction .
in addition , tsp-1 is selectively expressed in the infarcted border suggesting that tsp-1 might inhibit the expansion of the inflammation by activating tgf1 .   in the inflammatory processes leading to atherosclerosis ,
tsp-1 deficiency enhances inflammation by accelerating plaque maturation and necrosis in apoe - deficient mice .
however , tsp-1 expression is increased in response to high glucose in the wall of large vessels and accelerates atherosclerosis and other pathological events observed in diabetes .  
this correlation is explained by the tsp-1-dependent tgf1 activation that leads to upregulation of plasminogen activator inhibitor 1 ( pai-1 ) gene expression . elevated circulating pai-1 levels
mice lacking tsp-1 or the integrin 6 subunit ( tsp-1 and itgb6 mice , resp . )
the inflammation is not as severe as the one found in tgfb1 mice , which develop marked infiltrates of activated t cells in multiple organs and die soon after weaning .  
tsp-1 null mice have a more severe course of acute induced colitis ; they display increased bleeding and colonic inflammation compared to wt mice controls .  
tsp-1-deficient mice under multiple cycles of 2.5% of dextran sodium sulfate for induction of colitis die before the cycles are completed .
these mice show high incidence of megacolon and peritonitis due to the deeper infiltration of leukocytes into the muscularis and intestinal perforation . in order to increase survival ,
the use of the tsp - mimetic peptide abt510 drastically reduces intestinal inflammation and angiogenesis and enhances the expression of cd36 , which suggests that cd36 modulates inflammation in this model .
additionally , the interaction of tsp-1 with the no pathway seems to be involved in the antiangiogenic mechanisms mediated by the abt510 in cancers [ 31 , 69 ] , and it might also explain the anti - inflammatory effects of this peptide in the colitis model .
similarly , in a rat model with bleomycin - induced lung injury , a cd36 peptide also decreases inflammation and fibrosis in the lungs .  
a synthetic peptide derived from the tsp-1 type 3 repeats ( figure 1 ) also diminishes inflammation and angiogenesis in an experimental model of erosive arthritis . this peptide decreases angiogenesis , leukocyte infiltration , and thickening of the synovial lining of the joint . in the spleen and liver , this peptide significantly reduces the formation of granulomas .
however , tsp-1 is upregulated in monocytes , and tissues from patients with rheumatoid arthritis ( ra ) [ 74 , 75 ] and high plasmatic levels of tsp-1 are correlated with proinflammatory cytokines in these patients .  
tsp-1 also exerts proinflammatory effects in certain types of myositis [ 77 , 78 ] .
the chemotactic effect of tsp-1 in leukocytes by its binding to cd47 perpetuates the muscle inflammation in response to high levels of tnf - alpha .
in transplantation research , most of the corneal tsp-1 null allografts are rejected , suggesting a protolerogenic function [ 41 , 79 ] .
interestingly , when tsp-1 is inhibited by sirna - transfection in pancreatic islet cells , improved revascularization and function are observed in the pancreatic grafts .
antiangiogenic compounds , such as tsp-1 , might be useful for achieving a better perfusion and oxygenation in organ transplants .
it is involved in many biological processes such as inflammation , immunity , differentiation , cell growth , tumorigenesis , and apoptosis .
phosphorylation and subsequent degradation of ib releases nf-b and allows it to be translocated to the nucleus .
once inside the nucleus , this transcription factor induces its target genes , thereby inhibiting apoptosis , promoting inflammation , angiogenesis , and carcinogenesis .
importantly , nf-b activates the transcription of genes such as tnf - alpha and il-6 , which have major roles in regulating the immune response .
recently , it has been reported that blocking the activation of nf-b upregulates tsp-1 expression in rat granulation tissue .
tsp-1 has a major role in wound healing , and a significant delay of the healing process is observed in tsp-1 mice .
the link between tsp-1 and nf-b seems to be closely related to mechanisms of angiogenesis and carcinogenesis .
tsp-1 enhances the binding of nf-b to dna   inhibiting angiogenesis , and these events are reverted by blocking the nf-b pathway .
activation of nf-b by oxidized low - density lipoprotein ( oxldl ) , a specific ligand of cd36 , is reduced in macrophages of patients with cd36 deficiency .
studies in prostate cancers indicate that the combined decrease of nf-b and increase of tsp-1 , modulated by the expression of the androgen receptor , exert   antitumor effects   .
the tsp-1-derived peptide angiocidin has antitumor effects and induces the differentiation of monocytes to macrophages by activating the nf-b pathway . in response to cytokines and growth factors
, members of the stat family are phosphorylated by receptor - associated kinases forming homo- or heterodimers .
the lack of stat3 , the most important member of this family , actually leads to embryonic lethality .
stat3 mediates the expression of a variety of genes in response to cell stimuli and thus plays a key role in many cellular processes such as cell growth and apoptosis .
the binding of il-6 to the gp130 receptor triggers the phosphorylation of stat3 by jak2 [ 90 , 91 ] .  
it has been reported that downregulation of tgf1 in epithelial cells inhibits the secretion of il-6 . by this mechanism
furthermore , activated stat3 has been recently reported as crucial for intestinal carcinogenesis in colitis - associated cancer .
in addition , protein profiling of head and neck squamous carcinomas shows a significant decrease of several proteins such tsp-1 and tgf1 with concomitant increase of stat3 . in a model of angiogenesis , higher levels of il-6 are secreted by tsp-1 aortic explants , and similar results are found in a mouse model of colitis .
the higher levels of il-6 are lowered upon activation of tgf1 only in wt aortas .
the activity of il-6 was specifically examined through the stat3 pathway in colonic tissues evaluating the status of the phosphorylated forms of stat3 ( p - stat3 ) .  
interestingly , p - stat3 expression is highly expressed in tsp-1 colons and almost abolished in colons from mice treated with a new tsp-1-mimetic abt-898 ( abbott laboratories ) .
these data suggest that this mimetic peptide directly binds to tsp-1 receptors such as cd36 or indirectly interacts with other membrane domains to downregulate stat3 pathway , thereby depressing the immune response .  
therefore , activation of this pathway is critical for further activation of stat3 in colitis .
tsp-1 interacts with a variety of factors in a synergistic way , playing a crucial role in many stages of the inflammatory response .
we discussed herein the interactions of tsp-1 with well - known partners such as cd36 , cd47 , no , and tgf1 .
we also reviewed recent developments explaining how tsp-1 and its derived peptides directly or indirectly regulate inflammatory events in animal models and human diseases .  
leukocytes migrate to areas of injury or infection in elevated numbers ; similarly , tsp-1 is secreted at high levels in some areas in order to activate specific mechanisms for regulating the inflammatory response . in some cases
finally , new insights about key signaling pathways such as nf-b and stat3 were discussed . because chronic inflammation is linked with tumor development
, further studies analyzing the role of tsp-1 in these pathways could elucidate the similar contradictory functions of tsp-1 in cancer .
the unraveling of these mechanisms will make possible the development of new and more effective therapies for controlling inflammation and blocking carcinogenesis .
 inflammation is a defensive process against tissue injury . 
 once this self - protective strategy is initiated , an effective resolution of the process is crucial to avoid major and unnecessary tissue damage . 
 if the underlying event inducing inflammation is not addressed and homeostasis is not restored , this process can become chronic and lead to angiogenesis and carcinogenesis . 
 thrombospondin-1 ( tsp-1 ) is a matricellular protein involved in angiogenesis , cancer , and inflammation . 
 the effects of tsp-1 have been studied in many preclinical tumor models , and mimetic peptides are being tested in cancer clinical trials . 
 however , the molecular mechanisms explaining its role in inflammatory processes are not well understood . 
 this paper will discuss the role of tsp-1 in inflammation and its interaction with key receptors that may explain its functions in that process . 
 recent literature will be reviewed showing novel mechanisms by which this multifaceted protein could modulate the inflammatory process and impact its resolution . 