toll like receptor 4


Summary: A pattern recognition receptor that interacts with LYMPHOCYTE ANTIGEN 96 and LIPOPOLYSACCHARIDES. It mediates cellular responses to GRAM-NEGATIVE BACTERIA.

Top Publications

  1. Gong J, Wei T, Stark R, Jamitzky F, Heckl W, Anders H, et al. Inhibition of Toll-like receptors TLR4 and 7 signaling pathways by SIGIRR: a computational approach. J Struct Biol. 2010;169:323-30 pubmed publisher
    ..We suggest that SIGIRR may exert its inhibitory effect through blocking the molecular interface of TLR4, TLR7 and the MyD88 adaptor mainly via its BB-loop region. ..
  2. Wang S, Schmaderer C, Kiss E, Schmidt C, Bonrouhi M, Porubsky S, et al. Recipient Toll-like receptors contribute to chronic graft dysfunction by both MyD88- and TRIF-dependent signaling. Dis Model Mech. 2010;3:92-103 pubmed publisher
    ..A TLR signaling blockade may be a therapeutic option for the prevention of CAD. ..
  3. Dong J, Vallejo J, Tzeng H, Thomas J, Mann D. Innate immunity mediates myocardial preconditioning through Toll-like receptor 2 and TIRAP-dependent signaling pathways. Am J Physiol Heart Circ Physiol. 2010;298:H1079-87 pubmed publisher
  4. Senthilselvan A, Chenard L, Kirychuk S, Predicala B, Schwartz D, Burch L, et al. Gender-related tumor necrosis factor-alpha responses in naïve volunteers with Toll-like receptor 4 polymorphisms exposed in a swine confinement facility. J Interferon Cytokine Res. 2009;29:781-90 pubmed publisher
    ..These results suggest that for persons exposed to a swine facility, one's immunological response varies with gender as well as TLR4 genotype. ..
  5. Rusai K, Sollinger D, Baumann M, Wagner B, Strobl M, Schmaderer C, et al. Toll-like receptors 2 and 4 in renal ischemia/reperfusion injury. Pediatr Nephrol. 2010;25:853-60 pubmed publisher
    ..In conclusion, a double genetic deletion of TLR2 and TLR4 confers a similar protection following renal I/R injury compared with single deletions of TLR2 and TLR4. ..
  6. Yuan Z, Bennett L, Campo M, Nasir L. Bovine papillomavirus type 1 E2 and E7 proteins down-regulate Toll Like Receptor 4 (TLR4) expression in equine fibroblasts. Virus Res. 2010;149:124-7 pubmed publisher
    ..These data imply that BPV-1 is able to subvert the innate immune response by downregulation of TLR4...
  7. Numata M, Chu H, Dakhama A, Voelker D. Pulmonary surfactant phosphatidylglycerol inhibits respiratory syncytial virus-induced inflammation and infection. Proc Natl Acad Sci U S A. 2010;107:320-5 pubmed publisher
    ..These findings demonstrate an important approach to prevention and treatment of RSV infections using exogenous administration of a specific surfactant phospholipid. ..
  8. Maroso M, Balosso S, Ravizza T, Liu J, Aronica E, Iyer A, et al. Toll-like receptor 4 and high-mobility group box-1 are involved in ictogenesis and can be targeted to reduce seizures. Nat Med. 2010;16:413-9 pubmed publisher
    ..Thus, HMGB1-TLR4 signaling may contribute to generating and perpetuating seizures in humans and might be targeted to attain anticonvulsant effects in epilepsies that are currently resistant to drugs. ..
  9. Saberi M, Woods N, De Luca C, Schenk S, Lu J, Bandyopadhyay G, et al. Hematopoietic cell-specific deletion of toll-like receptor 4 ameliorates hepatic and adipose tissue insulin resistance in high-fat-fed mice. Cell Metab. 2009;10:419-29 pubmed publisher
    ..In summary, our results indicate that Tlr4 signaling in hematopoietic-derived cells is important for the development of hepatic and adipose tissue insulin resistance in obese mice. ..

More Information


  1. den Dekker W, Cheng C, Pasterkamp G, Duckers H. Toll like receptor 4 in atherosclerosis and plaque destabilization. Atherosclerosis. 2010;209:314-20 pubmed publisher
    ..In recent years there has been accumulating evidence for the involvement of Toll like receptor 4, a pattern recognition receptor of the innate immune system, in the pathogenesis of atherosclerosis...
  2. Elazar S, Gonen E, Livneh Kol A, Rosenshine I, Shpigel N. Neutrophil recruitment in endotoxin-induced murine mastitis is strictly dependent on mammary alveolar macrophages. Vet Res. 2010;41:10 pubmed publisher
  3. Prohinar P, Rallabhandi P, Weiss J, Gioannini T. Expression of functional D299G.T399I polymorphic variant of TLR4 depends more on coexpression of MD-2 than does wild-type TLR4. J Immunol. 2010;184:4362-7 pubmed publisher
    ..The dramatic effect of the D299G.T399I haplotype on expression of functional TLR4 without MD-2 suggests that cells expressing TLR4 without MD-2 are most affected by these polymorphisms. ..
  4. Ren M, Gao L, Wu X. TLR4: the receptor bridging Acanthamoeba challenge and intracellular inflammatory responses in human corneal cell lines. Immunol Cell Biol. 2010;88:529-36 pubmed publisher
    ..Thus, TLR4 is a receptor for Acanthamoeba and exerts an effect through TLR4-MyD88-NF-kappaB and TLR4-ERK1/2 pathways to induce the secretion of cytokines in human corneal cell lines challenged by Acanthamoeba. ..
  5. Javkhlan P, Hiroshima Y, Azlina A, Hasegawa T, Yao C, Akamatsu T, et al. Induction of calprotectin mRNAs by lipopolysaccharide in the salivary gland of mice. J Med Invest. 2009;56 Suppl:287-9 pubmed
    ..LPS injection induced calprotectin (S100A8/A9) in both duct and acinar cells especially in the former cells. ..
  6. Umenai T, Hirai H, Shime N, Nakaya T, Asahara T, Nomoto K, et al. Eradication of the commensal intestinal microflora by oral antimicrobials interferes with the host response to lipopolysaccharide. Eur J Clin Microbiol Infect Dis. 2010;29:633-41 pubmed publisher
    ..Our results suggest that the oral administration of antimicrobials downregulates the expression of surface TLR on the peritoneal macrophages and modulates the host immune responses against LPS by modifying the intestinal environment. ..
  7. Leal S, Cowden S, Hsia Y, Ghannoum M, Momany M, Pearlman E. Distinct roles for Dectin-1 and TLR4 in the pathogenesis of Aspergillus fumigatus keratitis. PLoS Pathog. 2010;6:e1000976 pubmed publisher
  8. Gollapudi P, Yoon J, Gollapudi S, Pahl M, Vaziri N. Leukocyte toll-like receptor expression in end-stage kidney disease. Am J Nephrol. 2010;31:247-54 pubmed publisher
    ..Monocyte TLR2 and TLR4 and neutrophil TLR4 expressions and TLR4 activity are increased hemodialysis patients, representing another dimension of ESRD-associated inflammation. ..
  9. Souza P, Palmqvist P, Lundgren I, Lie A, Costa Neto C, Lundberg P, et al. Stimulation of IL-6 cytokines in fibroblasts by toll-like receptors 2. J Dent Res. 2010;89:802-7 pubmed publisher
    ..Analysis of these data suggests that signaling through the innate immune system controls the expression of osteotropic cytokines in human gingival fibroblasts. ..
  10. Hernandez Y, Sotolongo J, Breglio K, Conduah D, Chen A, Xu R, et al. The role of prostaglandin E2 (PGE 2) in toll-like receptor 4 (TLR4)-mediated colitis-associated neoplasia. BMC Gastroenterol. 2010;10:82 pubmed publisher
    ..These results highlight the importance of PGE 2 as a central downstream molecule involving TLR4-mediated intestinal tumorigenesis. ..
  11. Hoshino S, Konishi M, Mori M, Shimura M, Nishitani C, Kuroki Y, et al. HIV-1 Vpr induces TLR4/MyD88-mediated IL-6 production and reactivates viral production from latency. J Leukoc Biol. 2010;87:1133-43 pubmed publisher
    ..Our results suggest that Vpr should be monitored based on the viral titer, and they provide the rationale for the development of novel, anti-AIDS therapeutics targeting Vpr. ..
  12. Hutchinson M, Lewis S, Coats B, Rezvani N, Zhang Y, Wieseler J, et al. Possible involvement of toll-like receptor 4/myeloid differentiation factor-2 activity of opioid inactive isomers causes spinal proinflammation and related behavioral consequences. Neuroscience. 2010;167:880-93 pubmed publisher
    ..Here, a structurally disparate range of opioids cause activation of signaling by the innate immune receptor toll like receptor 4 (TLR4), resulting in proinflammatory glial activation...
  13. Dietrich N, Rohde M, Geffers R, Kröger A, Hauser H, Weiss S, et al. Mast cells elicit proinflammatory but not type I interferon responses upon activation of TLRs by bacteria. Proc Natl Acad Sci U S A. 2010;107:8748-53 pubmed publisher
  14. Mandal P, Roychowdhury S, Park P, Pratt B, Roger T, Nagy L. Adiponectin and heme oxygenase-1 suppress TLR4/MyD88-independent signaling in rat Kupffer cells and in mice after chronic ethanol exposure. J Immunol. 2010;185:4928-37 pubmed publisher
    ..These data suggest that induction of HO-1 may be a useful therapeutic strategy in alcoholic liver disease...
  15. WILLIS L, Bielinski D, Fisher D, Matthan N, Joseph J. Walnut extract inhibits LPS-induced activation of BV-2 microglia via internalization of TLR4: possible involvement of phospholipase D2. Inflammation. 2010;33:325-33 pubmed publisher
    ..These studies represent the first to describe the anti-inflammatory effects of walnuts in microglia, which could lead to nutritional interventions in the prevention and treatment of neurodegeneration. ..
  16. Rudick C, Billips B, Pavlov V, Yaggie R, Schaeffer A, Klumpp D. Host-pathogen interactions mediating pain of urinary tract infection. J Infect Dis. 2010;201:1240-9 pubmed publisher
    ..Clinically, these findings also provide the rational for probiotic therapies that would minimize the symptoms of infection without reliance on empirical therapies that contribute to antimicrobial resistance. ..
  17. Konopka Ł, Wierzbicki M, Brzezińska Błaszczyk E. Lipopolysaccharide from Porphyromonas gingivalis stimulates rat mast cells to cysteinyl leukotriene generation and upregulates Toll-like receptor -2 and -4 expression. Int J Immunopathol Pharmacol. 2010;23:803-10 pubmed
  18. Dohnal A, Luger R, Paul P, Fuchs D, Felzmann T. CD40 ligation restores type 1 polarizing capacity in TLR4-activated dendritic cells that have ceased interleukin-12 expression. J Cell Mol Med. 2009;13:1741-50 pubmed
    ..These findings impact on the rational design of TLR-activated DC-based cancer vaccines for the induction of anti-tumoural CTL responses. ..
  19. Eissmann P, Evans J, Mehrabi M, Rose E, Nedvetzki S, Davis D. Multiple mechanisms downstream of TLR-4 stimulation allow expression of NKG2D ligands to facilitate macrophage/NK cell crosstalk. J Immunol. 2010;184:6901-9 pubmed publisher
    ..Thus, TLR stimulation allows expression of NKG2D ligands through multiple pathways, including downmodulation of specific miRNAs. ..
  20. Fernandez Jimenez N, Castellanos Rubio A, Plaza Izurieta L, Gutierrez G, Castano L, Vitoria J, et al. Analysis of beta-defensin and Toll-like receptor gene copy number variation in celiac disease. Hum Immunol. 2010;71:833-6 pubmed publisher
    ..023; odds ratio = 0.69, 95% CI = 0.50-0.96), suggesting that increased copy numbers could protect from CD, possibly by impeding bacterial infiltration more efficiently and preserving gut epithelial integrity. ..
  21. Miller Y, Choi S, Fang L, Tsimikas S. Lipoprotein modification and macrophage uptake: role of pathologic cholesterol transport in atherogenesis. Subcell Biochem. 2010;51:229-51 pubmed publisher
    ..Future directions in studying foam cell formation may include introducing novel animal models, such as hypercholesterolemic zebrafish, enabling dynamic in vivo observation of macrophage lipid uptake. ..
  22. Zheng B, Li Q, Wei C, Qin J, Shou T, Zhou R, et al. Lack of association of TLR4 gene Asp299Gly and Thr399Ile polymorphisms with rheumatoid arthritis in Chinese Han population of Yunnan Province. Rheumatol Int. 2010;30:1249-52 pubmed publisher
    ..Further studies with extended single nucleotide polymorphisms (SNP) should be performed. ..
  23. Ubagai T, Koshibu Y, Koshio O, Nakaki T, Ono Y. Downregulation of immunomodulator gene expression in LPS-stimulated human polymorphonuclear leukocytes by the proton pump inhibitor lansoprazole. J Infect Chemother. 2009;15:374-9 pubmed publisher
    ..01 microg/ml LPZ, in a dose-dependent manner. LPZ may suppress the biological functions of PMNs, such as chemotaxis and inflammatory chemokine production. ..
  24. Siednienko J, Halle A, Nagpal K, Golenbock D, Miggin S. TLR3-mediated IFN-? gene induction is negatively regulated by the TLR adaptor MyD88 adaptor-like. Eur J Immunol. 2010;40:3150-60 pubmed publisher
    ..Thus, Mal is essential in restricting TLR3 signalling thereby protecting the host from unwanted immunopathologies associated with excessive IFN-? production. ..
  25. Yu Z, Chen L, Wang Z, Xu N. [The expression of toll-like receptor4 and NF-kappaB in ulcerative colitis]. Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi. 2010;26:650-2 pubmed
    ..The expression of the TLR4 and NF-kappaB was increased in the colonic mucosa of UC compared with colonic mucosa of controls. It may be closely associated with the course of ulcerative colitis. ..
  26. Into T, Inomata M, Shibata K, Murakami Y. Effect of the antimicrobial peptide LL-37 on Toll-like receptors 2-, 3- and 4-triggered expression of IL-6, IL-8 and CXCL10 in human gingival fibroblasts. Cell Immunol. 2010;264:104-9 pubmed publisher
  27. Miller Y, Choi S, Fang L, Harkewicz R. Toll-like receptor-4 and lipoprotein accumulation in macrophages. Trends Cardiovasc Med. 2009;19:227-32 pubmed publisher
    ..A novel hypercholesterolemic zebrafish model of early stages of atherosclerosis was used to demonstrate that the TLR4 deficiency significantly reduces the in vivo rate of macrophage lipid accumulation in vascular lesions...
  28. Legat A, Thomas S, Hermand P, Van Mechelen M, Goldman M, De Wit D. CD14-independent responses induced by a synthetic lipid A mimetic. Eur J Immunol. 2010;40:797-802 pubmed publisher
    ..We conclude that the lipid A mimetic CRX-527 does not require the CD14 co-receptor to elicit TLR4-mediated responses. ..
  29. Deopurkar R, Ghanim H, Friedman J, Abuaysheh S, Sia C, Mohanty P, et al. Differential effects of cream, glucose, and orange juice on inflammation, endotoxin, and the expression of Toll-like receptor-4 and suppressor of cytokine signaling-3. Diabetes Care. 2010;33:991-7 pubmed publisher
    ..Equicaloric amounts of orange juice or water did not induce a change in any of these indexes. These changes are relevant to the pathogenesis of atherosclerosis and insulin resistance. ..
  30. Branco Madeira F, Lambrecht B. High mobility group box-1 recognition: the beginning of a RAGEless era?. EMBO Mol Med. 2010;2:193-5 pubmed publisher
    ..These reports add a new twist to our understanding of the mode of action of the alarm signal HMGB1. ..
  31. Sturges N, Wikstrom M, Winfield K, Gard S, Brennan S, Sly P, et al. Monocytes from children with clinically stable cystic fibrosis show enhanced expression of Toll-like receptor 4. Pediatr Pulmonol. 2010;45:883-9 pubmed publisher
    ..930). The increased surface expression of TLR4 seen in young children with CF appears to be related to having CF per se and not related to current pulmonary infection. ..
  32. Wang D, Lou J, Ouyang C, Chen W, Liu Y, Liu X, et al. Ras-related protein Rab10 facilitates TLR4 signaling by promoting replenishment of TLR4 onto the plasma membrane. Proc Natl Acad Sci U S A. 2010;107:13806-11 pubmed publisher
  33. Roger T, Casson N, Croxatto A, Entenza J, Pusztaszeri M, Akira S, et al. Role of MyD88 and Toll-like receptors 2 and 4 in the sensing of Parachlamydia acanthamoebae. Infect Immun. 2010;78:5195-201 pubmed publisher
    ..Thus, in contrast to Chlamydia pneumoniae, Parachlamydia acanthamoebae weakly stimulates macrophages, potentially compensating for its low replication capacity in macrophages by escaping the innate immune surveillance. ..
  34. Jin X, Qin Q, Tu L, Qu J. Glucocorticoids inhibit the innate immune system of human corneal fibroblast through their suppression of toll-like receptors. Mol Vis. 2009;15:2435-41 pubmed
    ..Our results suggest that topical glucocorticoids may affect the cornea's innate immunity through TLRs. ..
  35. Quevedo Diaz M, Song C, Xiong Y, Chen H, Wahl L, Radulovic S, et al. Involvement of TLR2 and TLR4 in cell responses to Rickettsia akari. J Leukoc Biol. 2010;88:675-85 pubmed publisher
    ..These data demonstrate that HK R. akari triggers cell activation via TLR2 or TLR4 and suggest use of additional TLRs and/or NLRs by live R. akari...
  36. Liao C, Wang S, Chen Y, Wang H, Wu J. Lipopolysaccharide-induced inhibition of connexin43 gap junction communication in astrocytes is mediated by downregulation of caveolin-3. Int J Biochem Cell Biol. 2010;42:762-70 pubmed publisher
    ..Our results suggest that long-term LPS treatment of astrocytes leads to inhibition of Cx43 gap junction communication by the activation of iNOS and downregulation of caveolin-3 via a TLR4-mediated signaling pathway. ..
  37. Li H, Sun X, Lesage G, Zhang Y, Liang Z, Chen J, et al. ?-arrestin 2 regulates Toll-like receptor 4-mediated apoptotic signalling through glycogen synthase kinase-3?. Immunology. 2010;130:556-63 pubmed publisher
  38. Maru Y. Premetastatic milieu explained by TLR4 agonist-mediated homeostatic inflammation. Cell Mol Immunol. 2010;7:94-9 pubmed publisher
    ..To explain the premetastatic microenvironment created by the newly discovered endogenous TLR4 ligands, I propose a hypothesis of homeostatic inflammation that includes the classical danger hypothesis. ..
  39. Sengupta D, Koblansky A, Gaines J, Brown T, West A, Zhang D, et al. Subversion of innate immune responses by Brucella through the targeted degradation of the TLR signaling adapter, MAL. J Immunol. 2010;184:956-64 pubmed publisher
    ..Therefore, TcpB represents a unique pathogen-derived molecule that suppresses host innate-immune responses by specifically targeting an individual adapter molecule in the TLR signaling pathway for degradation. ..
  40. Erridge C. Endogenous ligands of TLR2 and TLR4: agonists or assistants?. J Leukoc Biol. 2010;87:989-99 pubmed publisher
    ..The relevance of this possibility to the pathogenesis of chronic inflammatory diseases, tumor surveillance, and autoimmunity is discussed. ..
  41. Hong C, Qiu X, Li Y, Huang Q, Zhong Z, Zhang Y, et al. Functional analysis of recombinant calreticulin fragment 39-272: implications for immunobiological activities of calreticulin in health and disease. J Immunol. 2010;185:4561-9 pubmed publisher
    ..We argue that CRT, either on the membrane surface of cells or in soluble form, is a potent stimulatory molecule to B cells and macrophages via the TLR-4/CD14 pathway and plays important roles in the pathogenesis of autoimmune diseases. ..
  42. Chung W, An J, Yin L, Hacker B, Rohani M, Dommisch H, et al. Interplay of protease-activated receptors and NOD pattern recognition receptors in epithelial innate immune responses to bacteria. Immunol Lett. 2010;131:113-9 pubmed publisher
  43. Sun Y, Karmakar M, Roy S, Ramadan R, Williams S, Howell S, et al. TLR4 and TLR5 on corneal macrophages regulate Pseudomonas aeruginosa keratitis by signaling through MyD88-dependent and -independent pathways. J Immunol. 2010;185:4272-83 pubmed publisher
    ..IL-1? and IL-1? are also produced, which activate an IL-1R1/MyD88-positive feedback loop in macrophages and IL-1R on other resident cells in the cornea. ..
  44. Bhattacharjee R, Banerjee B, Akira S, Hande M. Telomere-mediated chromosomal instability triggers TLR4 induced inflammation and death in mice. PLoS ONE. 2010;5:e11873 pubmed publisher
    ..Chromosome/genomic instability data raises optimism for controlling inflammation by non-toxic TLR antagonists among high-risk groups. ..
  45. van Lent P, Grevers L, Schelbergen R, Blom A, Geurts J, Sloetjes A, et al. S100A8 causes a shift toward expression of activatory Fc? receptors on macrophages via toll-like receptor 4 and regulates Fc? receptor expression in synovium during chronic experimental arthritis. Arthritis Rheum. 2010;62:3353-64 pubmed publisher
    ..This study was undertaken to study the active involvement of S100A8, S100A9, and S100A8/S100A9 in Fc?R regulation in murine macrophages and synovium during AIA...
  46. Salam M, Katz J, Michalek S. Role of Toll-like receptors in host responses to a virulence antigen of Streptococcus mutans expressed by a recombinant, attenuated Salmonella vector vaccine. Vaccine. 2010;28:4928-36 pubmed
    ..Mucosal IgA responses to SBR were TLR2-, TLR4- and MyD88-dependent, while IgA responses to Salmonella were TLR4- and MyD88-dependent. ..
  47. Yamawaki Y, Kimura H, Hosoi T, Ozawa K. MyD88 plays a key role in LPS-induced Stat3 activation in the hypothalamus. Am J Physiol Regul Integr Comp Physiol. 2010;298:R403-10 pubmed publisher
    ..Taken together, our findings reveal a novel mechanism, i.e., MyD88 plays a key role in mediating STAT3 phosphorylation and anorexia in the CNS in a state of infection and inflammation. ..
  48. Tang H, Pang S, Wang M, Xiao X, Rong Y, Wang H, et al. TLR4 activation is required for IL-17-induced multiple tissue inflammation and wasting in mice. J Immunol. 2010;185:2563-9 pubmed publisher
    ..The study indicates a novel interaction between IL-17 and TLR4 activation and may have implications in the pathogenesis and treatment of chronic diseases. ..
  49. Mueller G, Edwards L, Aloor J, Fessler M, Glesner J, Pomés A, et al. The structure of the dust mite allergen Der p 7 reveals similarities to innate immune proteins. J Allergy Clin Immunol. 2010;125:909-917.e4 pubmed publisher
    ..The finding that the group 7, as well as the group 2, mite allergens are structurally similar to different proteins in the Toll-like receptor pathway further strengthens the connections between dust mites, innate immunity, and allergy. ..
  50. Lambrianides A, Carroll C, Pierangeli S, Pericleous C, Branch W, Rice J, et al. Effects of polyclonal IgG derived from patients with different clinical types of the antiphospholipid syndrome on monocyte signaling pathways. J Immunol. 2010;184:6622-8 pubmed publisher
  51. Wang L, Zhang X, Liu L, Cui L, Yang R, Li M, et al. Tanshinone II A down-regulates HMGB1, RAGE, TLR4, NF-kappaB expression, ameliorates BBB permeability and endothelial cell function, and protects rat brains against focal ischemia. Brain Res. 2010;1321:143-51 pubmed publisher
    ..Tan II A protected the brain from damage caused by pMCAO; this effect may be through down-regulation of HMGB1, RAGE and TLR4, NF-kappaB and up-regulation claudin-5 expression...
  52. Sheedy F, Palsson McDermott E, Hennessy E, Martin C, O Leary J, Ruan Q, et al. Negative regulation of TLR4 via targeting of the proinflammatory tumor suppressor PDCD4 by the microRNA miR-21. Nat Immunol. 2010;11:141-7 pubmed publisher
    ..Thus, miR-21 regulates PDCD4 expression after LPS stimulation. ..
  53. Zanchi N, Lira F, de Siqueira Filho M, Rosa J, de Oliveira Carvalho C, Seelaender M, et al. Chronic low frequency/low volume resistance training reduces pro-inflammatory cytokine protein levels and TLR4 mRNA in rat skeletal muscle. Eur J Appl Physiol. 2010;109:1095-102 pubmed publisher