Global expression profiling of theophylline response genes in macrophages: evidence of airway anti-inflammatory regulation.
BACKGROUND
Theophylline has been used widely as a bronchodilator for the treatment of bronchial asthma and has been suggested to modulate immune response. While the importance of macrophages in asthma has been reappraised and emphasized, their significance has not been well investigated. We conducted a genome-wide profiling of the gene expressions of macrophages in response to theophylline.


METHODS
Microarray technology was used to profile the gene expression patterns of macrophages modulated by theophylline. Northern blot and real-time quantitative RT-PCR were also used to validate the microarray data, while Western blot and ELISA were used to measure the levels of IL-13 and LTC4.


RESULTS
We identified dozens of genes in macrophages that were dose-dependently down- or up-regulated by theophylline. These included genes related to inflammation, cytokines, signaling transduction, cell adhesion and motility, cell cycle regulators, and metabolism. We observed that IL-13, a central mediator of airway inflammation, was dramatically suppressed by theophylline. Real-time quantitative RT-PCR and ELISA analyses also confirmed these results, without respect to PMA-treated THP-1 cells or isolated human alveolar macrophages. Theophylline, rolipram, etazolate, db-cAMP and forskolin suppressed both IL-13 mRNA expression (~25%, 2.73%, 8.12%, 5.28%, and 18.41%, respectively) and protein secretion (<10% production) in macrophages. These agents also effectively suppressed LTC4 expression.


CONCLUSIONS
Our results suggest that the suppression of IL-13 by theophylline may be through cAMP mediation and may decrease LTC4 production. This study supports the role of theophylline as a signal regulator of inflammation, and that down regulation of IL-13 by theophylline may have beneficial effects in inflammatory airway diseases.
Yao
Pei-Li
PL
Department of Internal Medicine, National Taiwan University Hospital, Taipei 100, Taiwan. dalen@mail.utexas.edu
Tsai
Meng-Feng
MF
Lin
Yi-Chen
YC
Wang
Chien-Hsun
CH
Liao
Wei-Yu
WY
Chen
Jeremy J W
JJ
Yang
Pan-Chyr
PC
D000893:Anti-Inflammatory Agents / Q000008:administration & dosage; D001991:Bronchitis / Q000378:metabolism* / Q000473:pathology*; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007155:Immunologic Factors / Q000378:metabolism*; D018793:Interleukin-13 / Q000378:metabolism; D017997:Leukotriene C4 / Q000378:metabolism; D008262:Macrophage Activation / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D020543:Proteome / Q000378:metabolism; D011650:Pulmonary Alveoli / Q000378:metabolism* / Q000473:pathology; D013806:Theophylline / Q000008:administration & dosage*
D000893:Anti-Inflammatory Agents; D007155:Immunologic Factors; D018793:Interleukin-13; D020543:Proteome; D017997:Leukotriene C4; D013806:Theophylline