Pdcd4 modulates markers of macrophage alternative activation and airway remodeling in antigen-induced pulmonary inflammation

J Leukoc Biol. 2014 Dec;96(6):1065-75. doi: 10.1189/jlb.3A0313-136RRR. Epub 2014 Aug 5.


Pdcd4 has been known as a tumor-suppressor gene initially and is up-regulated during apoptosis. Surprisingly, we found that Pdcd4 was differentially expressed in the lung from E3 rats with AIPI, an animal model for asthma, but the precise role of Pdcd4 in AIPI still remained to be defined. In the present study, we first evaluated the expression of Pdcd4 in lung from control and AIPI rats with RT-qPCR, Western blot, and immunohistochemistry. Then, we investigated the effects of intervention of Pdcd4 on markers of macrophage alternative activation and airway remodeling. Upon challenging E3 rats with OVA, Pdcd4 was up-regulated in lung tissue with AIPI. Immunohistochemistry results showed that alveolar macrophages and airway epithelia expressed Pdcd4 protein. Overexpression of Pdcd4 in the rat alveolar macrophage cell line, NR8383 cells, increased the mRNA expression of arginase-1 and TGF-β1, which are markers of macrophage alternative activation. In response to Pdcd4 RNAi in NR8383 cells, the mRNA expression of markers Fizz1, Ym1/2, arginase-1, and TGF-β1 was decreased significantly. In addition, Pdcd4 RNAi in AIPI rats led to a decrease of the mRNA expression of Fizz1, Ym1/2, arginase-1, and TGF-β1 in BALF cells. Finally, knockdown of Pdcd4 suppressed airway eosinophil infiltration, bronchus collagen deposition, and mucus production. Overall, these results suggest that Pdcd4 may be worthy of further investigation as a target for macrophage alternative activation and airway remodeling in allergic pulmonary inflammation.

Keywords: M2 macrophage; asthma; programmed cell death 4.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Airway Remodeling / immunology
  • Airway Remodeling / physiology*
  • Animals
  • Apoptosis Regulatory Proteins / antagonists & inhibitors
  • Apoptosis Regulatory Proteins / biosynthesis
  • Apoptosis Regulatory Proteins / genetics
  • Apoptosis Regulatory Proteins / physiology*
  • Arginase / biosynthesis
  • Arginase / genetics
  • Asthma / drug therapy
  • Asthma / immunology
  • Asthma / pathology
  • Biomarkers
  • Bronchoalveolar Lavage Fluid
  • Cell Line
  • Disease Models, Animal
  • Gene Expression Regulation / drug effects
  • Lung / metabolism
  • Lung / pathology
  • Macrophage Activation / drug effects*
  • Macrophages, Alveolar / drug effects
  • Macrophages, Alveolar / physiology*
  • Mucus / metabolism
  • Nerve Growth Factor / biosynthesis
  • Nerve Growth Factor / genetics
  • Ovalbumin / toxicity
  • RNA Interference
  • RNA, Small Interfering / pharmacology
  • RNA, Small Interfering / therapeutic use
  • Rats
  • Spleen / metabolism
  • Transforming Growth Factor beta1 / biosynthesis
  • Transforming Growth Factor beta1 / genetics
  • beta-N-Acetylhexosaminidases / biosynthesis
  • beta-N-Acetylhexosaminidases / genetics


  • Apoptosis Regulatory Proteins
  • Biomarkers
  • Pdcd4 protein, rat
  • RNA, Small Interfering
  • Retnla protein, rat
  • Transforming Growth Factor beta1
  • Ovalbumin
  • Nerve Growth Factor
  • beta-N-Acetylhexosaminidases
  • Arginase