IL-4 inhibits expression of the formyl peptide receptor gene in mouse peritoneal macrophages.
Regulation of leukocyte recruitment is an important determinant of the host response to microbial infection. Because tissue infiltration by inflammatory cells represents a potential source of unnecessary tissue damage, the process may be controlled by modulating the expression of chemoattractants and the receptors through which they promote directed leukocyte migration. In the present report, we show that expression of the receptor for chemotactic formylated peptides (FPR1)is negatively regulated in both macrophages and neutrophils by interleukin-4 (IL-4). The reduction of FPR1 mRNA occurs rapidly in response to both IL-4 and IL-13 but endures for <4 h after the removal of IL-4. As with many other responses to IL-4 and IL-13, suppression of FPR1 expression is dependent on the activation of Stat6. The inhibitory effect exhibits relative stimulus specificity in that other Stat-activating cytokines, such as interferon-gamma (IFN-gamma), IFN-beta, and IL-10, have no effect. Using nuclear run-on analysis, the rate of FPR1 gene transcription is high but is not suppressed by IL-4. Moreover, IL-4 does not appear to alter the rate of FPR mRNA decay. Nevertheless, FPR mRNA exhibits a short half-life (< or =2 h), and this appears to be a critical feature of the ability of IL-4 to reduce expression. Taken together, the data suggest that IL-4 and IL-13 suppress the expression of FPR1 mRNA via a mechanism that operates to eliminate primary transcripts prior to maturation and depends on the constitutive instability of preexisiting mRNA.
Dai
Yalei
Y
Department of Immunology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA.
Major
Jennifer
J
Novotny
Michael
M
Hamilton
Thomas A
TA
D000818:Animals; D005786:Gene Expression Regulation / Q000502:physiology*; D015847:Interleukin-4 / Q000378:metabolism*; D017737:Macrophages, Peritoneal / Q000378:metabolism*; D051379:Mice; D012333:RNA, Messenger / Q000378:metabolism; D044042:Receptors, Formyl Peptide / Q000096:biosynthesis / Q000235:genetics*; D050800:STAT6 Transcription Factor; D015534:Trans-Activators / Q000378:metabolism
C469988:Fpr1 protein, mouse; D012333:RNA, Messenger; D044042:Receptors, Formyl Peptide; D050800:STAT6 Transcription Factor; C494100:Stat6 protein, mouse; D015534:Trans-Activators; D015847:Interleukin-4