Regulation of IL-13 production by histamine in cloned murine T helper type 2 cells

Kathleen A. Elliott, Natalia A. Osna, Margaret A. Scofield, Manzoor M. Khan

Research output: Contribution to journalArticle

38 Scopus citations

Abstract

Histamine affects the balance of T helper type 1 (Th1) and T helper type 2 (Th2) cytokines by shifting cytokine production from a Th1 to a Th2 pattern. Interleukin-13 (IL-13) is an important autacoid mediator that has been implicated in the development of allergic disease. This study was designed to investigate the mechanisms of regulation of IL-13 by histamine in Th2 cells. D10.G4.1 cells, a murine Th2 cell line, were treated with histamine (10-8-10-4 M) and then activated with PMA (phorbol 12 myristate 13-acetate) plus ionomycin or αCD3. Levels of IL-13 production were then measured by enzyme-linked immunosorbent assay (ELISA) and semiquantitative reverse transcription-polymerase chain reaction (RT-PCR). Cells were pretreated with histamine receptor antagonists pyrilamine, ranitidine, cimetidine and thioperamide to determine the involvement of histamine receptors. Cells were also pretreated with protein kinase A (PKA) inhibitors N-[2-(methylaminoethyl)]-5-isoquinoline-sulfonamide (H-8) and Rp-diastereomer of adenosine cyclic 3′5′-phosphorothionate (Rp-cAMPS), and Janus kinase-signal transducer and activator of transcription (Jak-STAT) inhibitor tyrphostin AG490 prior to the addition of histamine. H-8 is an inhibitor of the catalytic subunit of PKA while Rp-cAMPS is an inhibitor of the regulatory subunit of PKA. Tyrphostin is an inhibitor of Jak2, Jak3, STAT1, STAT3 and STAT5. Finally, cells were pretreated with IL-12, a monokine known to repress STAT6 DNA binding. We found that histamine dose-dependently enhanced IL-13 secretion and mRNA levels in Th2 cells via H1 and H2 receptors. Pretreatment of cells with H-8, Rp-cAMPS and tyrphostin prevented histamine-induced secretion and transcription of IL-13. Likewise, pretreatment of Th2 cells with IL-12 also reversed histamine's effects on IL-13 secretion from stimulatory to inhibitory. These observations suggest a role for PKA and the Jak-STAT pathway in histamine-mediated elevation of IL-13 secretion and transcription.

Original languageEnglish (US)
Pages (from-to)1923-1937
Number of pages15
JournalInternational Immunopharmacology
Volume1
Issue number11
DOIs
StatePublished - 2001

Keywords

  • H-8
  • Histamine
  • Interleukin-12
  • Interleukin-13
  • Janus kinase
  • Protein kinase A
  • Rp-cAMPS
  • STAT6
  • Th2 lymphocytes
  • Tyrphostin AG490

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Pharmacology

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