title: Gene expression profiles identify both MyD88-independent and MyD88-dependent pathways involved in the maturation of dendritic cells mediated by heparan sulfate: a novel adjuvant.
abstract: The traditional vaccine adjuvant research is mainly based on the trial and error method, and the mechanisms underlying the immune system stimulation remaining largely unknown. We previously demonstrated that heparan sulfate (HS), a TLR-4 ligand and endogenous danger signal, effectively enhanced humoral and cellular immune responses in mice immunized by HBsAg. This study aimed to evaluate whether HS induces better humoral immune responses against inactivated Hepatitis A or Rabies Vaccines, respectively, compared with traditional adjuvants (e.g. Alum and complete Freund's adjuvant). In order to investigate the molecular mechanisms of its adjuvanticity, the gene expression pattern of peripheral blood monocytes derived DCs (dendritic cells) stimulated with HS was analyzed at different times points. Total RNA was hybridized to Agilent SurePrint G3 Human Gene Expression 8×60 K one-color oligo-microarray. Through intersection analysis of the microarray results, we found that the Toll-like receptor signaling pathway was significantly activated, and NF-kB, TRAF3 and IRF7 were activated as early as 12 h, and MyD88 was activated at 48 h post-stimulation. Furthermore, the expression of the surface marker CD83 and the co-stimulatory molecules CD80 and CD86 was up-regulated as early as 24 h. Therefore, we speculated that HS-induced human monocyte-derived DC maturation may occur through both MyD88-independent and dependent pathways, but primarily through the former (TRIF pathway). These data provide an important basis for understanding the mechanisms underlying HS enhancement of the immune response.
authors: a Institute of Medical Biology; Chinese Academy of Medical Sciences and Peking Union Medical College ; Kunming , China.
authors: Meini
authors: M
authors: Wu
authors: Haixuan
authors: H
authors: Wang
authors: Jiandong
authors: J
authors: Shi
authors: Jing
authors: J
authors: Sun
authors: Zhiqing
authors: Z
authors: Duan
authors: Yanhan
authors: Y
authors: Li
authors: Jianfang
authors: J
authors: Li
authors: Ningzhu
authors: N
authors: Hu
authors: Yiju
authors: Y
authors: Wei
authors: Yang
authors: Y
authors: Chen
authors: Yunzhang
authors: Y
authors: Hu
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000818:Animals; D003713:Dendritic Cells / Q000502:physiology*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006497:Heparan Sulfate / Q000494:pharmacology*; D051379:Mice; D008813:Mice, Inbred ICR; D053594:Myeloid Differentiation Factor 88 / Q000502:physiology*; D020411:Oligonucleotide Array Sequence Analysis; D011819:Rabies Vaccines / Q000276:immunology; D051193:Toll-Like Receptors / Q000502:physiology; D059467:Transcriptome
chemical_list: D000276:Adjuvants, Immunologic; D006497:Heparan Sulfate; D053594:Myeloid Differentiation Factor 88; D011819:Rabies Vaccines; D051193:Toll-Like Receptors; C507780:Myd88 protein, mouse
keywords: DCs, Dendritic cells; DEGs, differentially expressed genes; GO, Gene Ontology; HAV, hepatitis A virus; HBsAg, hepatitis B surface antigen; HS, heparan sulfate; IRF7, interferon regulatory factor 7; KEGG, Kyoto Encyclopedia of Genes and Genomes; MyD88, myeloid differentiation primary response 88; NF-kB, nuclear factor-kappa B; Rab/Vac, Rabies Vaccine; TRAF3, TNF receptor-associated factor 3; dendritic cells; gene expression profile; heparan sulfate; humoral immune response; toll-like receptor signaling pathway; vaccine adjuvant