• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information
Logo of amjpatholAmerican Journal of Pathology For AuthorsAmerican Journal of Pathology SubscribeAmerican Journal of Pathology SearchAmerican Journal of Pathology Current IssueAmerican Journal of Pathology About the JournalAmerican Journal of Pathology
Am J Pathol. Aug 1997; 151(2): 375–387.
PMCID: PMC1858005

RelB regulation of chemokine expression modulates local inflammation.


The resolution of acute inflammation is incompletely understood but presumably requires the elimination of both inflammatory cells and production of inflammatory cytokines. In the case of recruited bone-marrow-derived inflammatory cells such as granulocytes and macrophages, their short life span helps eliminate these cells and the cytokines they produce. By contrast, resident permanent cells such as fibroblasts require other mechanisms to stop the production of chemokines generated in response to inflammatory triggers such as lipopolysaccharide. Here we demonstrate that RelB is an important regulator of chemokine expression in fibroblasts, thereby playing a key role in the resolution of acute inflammation. Activation of normal fibroblasts by lipopolysaccharide induced a transient production of chemokines, closely followed by induction of RelB expression. However, stimulated RelB-/- fibroblasts exhibited dramatic persistent induction of seven chemokines (RANTES, MIP-1 alpha, MIP-1 beta, MIP-2, IP-10, JE/MCP-1, and KC/CINC). The persistent overexpression of chemokines correlated with increased NF- kappa B binding as well as with increased p50, p65/RelA, and I kappa B alpha expression. Transfection of RelB cDNA into RelB-deficient fibroblasts reversed the lipopolysaccharide-induced chemokine overexpression. In vivo, activated RelB-/- fibroblasts dramatically increased recruitment of granulocytes into tissues. In view of the apparent role of RelB in the resolution of acute inflammation in tissues and previous work showing a requirement for RelB in the initiation of immune responses through the differentiation of antigen-presenting cells, RelB may be an important factor regulating the transition from innate to adaptive immunity.

Full text

Full text is available as a scanned copy of the original print version. Get a printable copy (PDF file) of the complete article (4.0M), or click on a page image below to browse page by page. Links to PubMed are also available for Selected References.

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Vaddi K, Newton RC. Regulation of monocyte integrin expression by beta-family chemokines. J Immunol. 1994 Nov 15;153(10):4721–4732. [PubMed]
  • Rot A. Neutrophil attractant/activation protein-1 (interleukin-8) induces in vitro neutrophil migration by haptotactic mechanism. Eur J Immunol. 1993 Jan;23(1):303–306. [PubMed]
  • Geiser T, Dewald B, Ehrengruber MU, Clark-Lewis I, Baggiolini M. The interleukin-8-related chemotactic cytokines GRO alpha, GRO beta, and GRO gamma activate human neutrophil and basophil leukocytes. J Biol Chem. 1993 Jul 25;268(21):15419–15424. [PubMed]
  • Walz A, Meloni F, Clark-Lewis I, von Tscharner V, Baggiolini M. [Ca2+]i changes and respiratory burst in human neutrophils and monocytes induced by NAP-1/interleukin-8, NAP-2, and gro/MGSA. J Leukoc Biol. 1991 Sep;50(3):279–286. [PubMed]
  • Sylvester I, Suffredini AF, Boujoukos AJ, Martich GD, Danner RL, Yoshimura T, Leonard EJ. Neutrophil attractant protein-1 and monocyte chemoattractant protein-1 in human serum. Effects of intravenous lipopolysaccharide on free attractants, specific IgG autoantibodies and immune complexes. J Immunol. 1993 Sep 15;151(6):3292–3298. [PubMed]
  • Chaudhuri A, Zbrzezna V, Polyakova J, Pogo AO, Hesselgesser J, Horuk R. Expression of the Duffy antigen in K562 cells. Evidence that it is the human erythrocyte chemokine receptor. J Biol Chem. 1994 Mar 18;269(11):7835–7838. [PubMed]
  • Furie MB, Randolph GJ. Chemokines and tissue injury. Am J Pathol. 1995 Jun;146(6):1287–1301. [PMC free article] [PubMed]
  • Beg AA, Sha WC, Bronson RT, Ghosh S, Baltimore D. Embryonic lethality and liver degeneration in mice lacking the RelA component of NF-kappa B. Nature. 1995 Jul 13;376(6536):167–170. [PubMed]
  • Baeuerle PA, Baltimore D. NF-kappa B: ten years after. Cell. 1996 Oct 4;87(1):13–20. [PubMed]
  • Burkly L, Hession C, Ogata L, Reilly C, Marconi LA, Olson D, Tizard R, Cate R, Lo D. Expression of relB is required for the development of thymic medulla and dendritic cells. Nature. 1995 Feb 9;373(6514):531–536. [PubMed]
  • Weih F, Carrasco D, Durham SK, Barton DS, Rizzo CA, Ryseck RP, Lira SA, Bravo R. Multiorgan inflammation and hematopoietic abnormalities in mice with a targeted disruption of RelB, a member of the NF-kappa B/Rel family. Cell. 1995 Jan 27;80(2):331–340. [PubMed]
  • Baldwin AS., Jr The NF-kappa B and I kappa B proteins: new discoveries and insights. Annu Rev Immunol. 1996;14:649–683. [PubMed]
  • Ryseck RP, Bull P, Takamiya M, Bours V, Siebenlist U, Dobrzanski P, Bravo R. RelB, a new Rel family transcription activator that can interact with p50-NF-kappa B. Mol Cell Biol. 1992 Feb;12(2):674–684. [PMC free article] [PubMed]
  • Lernbecher T, Kistler B, Wirth T. Two distinct mechanisms contribute to the constitutive activation of RelB in lymphoid cells. EMBO J. 1994 Sep 1;13(17):4060–4069. [PMC free article] [PubMed]
  • Grilli M, Chiu JJ, Lenardo MJ. NF-kappa B and Rel: participants in a multiform transcriptional regulatory system. Int Rev Cytol. 1993;143:1–62. [PubMed]
  • Baeuerle PA, Henkel T. Function and activation of NF-kappa B in the immune system. Annu Rev Immunol. 1994;12:141–179. [PubMed]
  • Widmer U, Manogue KR, Cerami A, Sherry B. Genomic cloning and promoter analysis of macrophage inflammatory protein (MIP)-2, MIP-1 alpha, and MIP-1 beta, members of the chemokine superfamily of proinflammatory cytokines. J Immunol. 1993 Jun 1;150(11):4996–5012. [PubMed]
  • Beg AA, Sha WC, Bronson RT, Baltimore D. Constitutive NF-kappa B activation, enhanced granulopoiesis, and neonatal lethality in I kappa B alpha-deficient mice. Genes Dev. 1995 Nov 15;9(22):2736–2746. [PubMed]
  • Lo D, Quill H, Burkly L, Scott B, Palmiter RD, Brinster RL. A recessive defect in lymphocyte or granulocyte function caused by an integrated transgene. Am J Pathol. 1992 Nov;141(5):1237–1246. [PMC free article] [PubMed]
  • Feng L, Xia Y, Kreisberg JI, Wilson CB. Interleukin-1 alpha stimulates KC synthesis in rat mesangial cells: glucocorticoids inhibit KC induction by IL-1. Am J Physiol. 1994 May;266(5 Pt 2):F713–F722. [PubMed]
  • Chomczynski P, Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987 Apr;162(1):156–159. [PubMed]
  • Dignam JD, Lebovitz RM, Roeder RG. Accurate transcription initiation by RNA polymerase II in a soluble extract from isolated mammalian nuclei. Nucleic Acids Res. 1983 Mar 11;11(5):1475–1489. [PMC free article] [PubMed]
  • DeKoning J, DiMolfetto L, Reilly C, Wei Q, Havran WL, Lo D. Thymic cortical epithelium is sufficient for the development of mature T cells in relB-deficient mice. J Immunol. 1997 Mar 15;158(6):2558–2566. [PubMed]
  • Laufer TM, DeKoning J, Markowitz JS, Lo D, Glimcher LH. Unopposed positive selection and autoreactivity in mice expressing class II MHC only on thymic cortex. Nature. 1996 Sep 5;383(6595):81–85. [PubMed]
  • Schall TJ, Bacon KB. Chemokines, leukocyte trafficking, and inflammation. Curr Opin Immunol. 1994 Dec;6(6):865–873. [PubMed]
  • Ito CY, Kazantsev AG, Baldwin AS., Jr Three NF-kappa B sites in the I kappa B-alpha promoter are required for induction of gene expression by TNF alpha. Nucleic Acids Res. 1994 Sep 11;22(18):3787–3792. [PMC free article] [PubMed]
  • Sun SC, Ganchi PA, Ballard DW, Greene WC. NF-kappa B controls expression of inhibitor I kappa B alpha: evidence for an inducible autoregulatory pathway. Science. 1993 Mar 26;259(5103):1912–1915. [PubMed]
  • Dobrzanski P, Ryseck RP, Bravo R. Both N- and C-terminal domains of RelB are required for full transactivation: role of the N-terminal leucine zipper-like motif. Mol Cell Biol. 1993 Mar;13(3):1572–1582. [PMC free article] [PubMed]
  • Bours V, Azarenko V, Dejardin E, Siebenlist U. Human RelB (I-Rel) functions as a kappa B site-dependent transactivating member of the family of Rel-related proteins. Oncogene. 1994 Jun;9(6):1699–1702. [PubMed]
  • Lernbecher T, Müller U, Wirth T. Distinct NF-kappa B/Rel transcription factors are responsible for tissue-specific and inducible gene activation. Nature. 1993 Oct 21;365(6448):767–770. [PubMed]
  • Dobrzanski P, Ryseck RP, Bravo R. Specific inhibition of RelB/p52 transcriptional activity by the C-terminal domain of p100. Oncogene. 1995 Mar 2;10(5):1003–1007. [PubMed]
  • Cheng Q, Cant CA, Moll T, Hofer-Warbinek R, Wagner E, Birnstiel ML, Bach FH, de Martin R. NK-kappa B subunit-specific regulation of the I kappa B alpha promoter. J Biol Chem. 1994 May 6;269(18):13551–13557. [PubMed]
  • Bombara MP, Webb DL, Conrad P, Marlor CW, Sarr T, Ranges GE, Aune TM, Greve JM, Blue ML. Cell contact between T cells and synovial fibroblasts causes induction of adhesion molecules and cytokines. J Leukoc Biol. 1993 Nov;54(5):399–406. [PubMed]
  • Mauviel A, Reitamo S, Remitz A, Lapière JC, Ceska M, Baggiolini M, Walz A, Evans CH, Uitto J. Leukoregulin, a T cell-derived cytokine, induces IL-8 gene expression and secretion in human skin fibroblasts. Demonstration and secretion in human skin fibroblasts. Demonstration of enhanced NF-kappa B binding and NF-kappa B-driven promoter activity. J Immunol. 1992 Nov 1;149(9):2969–2976. [PubMed]
  • Weih F, Lira SA, Bravo R. Overexpression of RelB in transgenic mice does not affect I kappa B alpha levels: differential regulation of RelA and RelB by the inhibitor protein. Oncogene. 1996 Jan 18;12(2):445–449. [PubMed]
  • Kulkarni AB, Huh CG, Becker D, Geiser A, Lyght M, Flanders KC, Roberts AB, Sporn MB, Ward JM, Karlsson S. Transforming growth factor beta 1 null mutation in mice causes excessive inflammatory response and early death. Proc Natl Acad Sci U S A. 1993 Jan 15;90(2):770–774. [PMC free article] [PubMed]
  • Shull MM, Ormsby I, Kier AB, Pawlowski S, Diebold RJ, Yin M, Allen R, Sidman C, Proetzel G, Calvin D, et al. Targeted disruption of the mouse transforming growth factor-beta 1 gene results in multifocal inflammatory disease. Nature. 1992 Oct 22;359(6397):693–699. [PMC free article] [PubMed]

Articles from The American Journal of Pathology are provided here courtesy of American Society for Investigative Pathology


Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...


  • Cited in Books
    Cited in Books
    PubMed Central articles cited in books
  • MedGen
    Related information in MedGen
  • PubMed
    PubMed citations for these articles
  • Substance
    PubChem Substance links

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...