MicroRNA-98 and let-7 confer cholangiocyte expression of cytokine-inducible Src homology 2-containing protein in response to microbial challenge

Guoku Hu, Rui Zhou, Jun Liu, Ai Y. Gong, Alex N. Eischeid, Jared W. Dittman, Xian-Ming Chen

Research output: Contribution to journalArticle

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Abstract

Posttranscriptional gene regulation by microRNAs (miRNAs) has been implicated in the fine-tuning of TLR-mediated inflammatory response. The cytokine-inducible Src homology 2-containing protein (CIS), one member of the suppressors of cytokine signaling family of proteins, is an important negative regulator for inflammatory cytokine signaling. Using in vitro models using normal human biliary epithelial cells (cholangiocytes), we demonstrated that LPS stimulation or infection with the parasitic protozoan Cryptosporidium parvum induced expression of CIS protein without a change in CIS mRNA levels by activating the TLR signaling pathway. Of those miRNAs expressed in cholangiocytes, we found that targeting of the 3′-untranslated region of CIS by microRNA-98 (miR-98) or let-7 resulted in translational repression, but not CIS mRNA degradation. LPS stimulation or C. parvum infection decreased cholangiocyte expression of miR-98 and let-7. Down-regulation of miR-98 and let-7 relieved miRNA-mediated translational suppression of CIS and contributed to LPS- and C. parvum-stimulated CIS protein expression. Moreover, gain-of-function (by overexpression of CIS) and loss-of-function (by siRNA interference) studies revealed that CIS could enhance IκBα degradation and regulate NF-κB activation in cholangiocytes in response to LPS stimulation or C. parvum infection. Our data suggest that miR-98 and let-7 confer cholangiocyte expression of CIS in response to microbial challenge, a process that may be relevant to the regulation of TLR-mediated epithelial innate immune response.

Original languageEnglish
Pages (from-to)1617-1624
Number of pages8
JournalJournal of Immunology
Volume183
Issue number3
DOIs
StatePublished - Aug 1 2009

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MicroRNAs
Cryptosporidium parvum
Cytokines
Proteins
Suppressor of Cytokine Signaling Proteins
Parasitic Diseases
RNA Stability
3' Untranslated Regions
Infection
Innate Immunity
Small Interfering RNA
Down-Regulation
Epithelial Cells
Messenger RNA
Genes

All Science Journal Classification (ASJC) codes

  • Immunology
  • Medicine(all)

Cite this

MicroRNA-98 and let-7 confer cholangiocyte expression of cytokine-inducible Src homology 2-containing protein in response to microbial challenge. / Hu, Guoku; Zhou, Rui; Liu, Jun; Gong, Ai Y.; Eischeid, Alex N.; Dittman, Jared W.; Chen, Xian-Ming.

In: Journal of Immunology, Vol. 183, No. 3, 01.08.2009, p. 1617-1624.

Research output: Contribution to journalArticle

Hu, Guoku ; Zhou, Rui ; Liu, Jun ; Gong, Ai Y. ; Eischeid, Alex N. ; Dittman, Jared W. ; Chen, Xian-Ming. / MicroRNA-98 and let-7 confer cholangiocyte expression of cytokine-inducible Src homology 2-containing protein in response to microbial challenge. In: Journal of Immunology. 2009 ; Vol. 183, No. 3. pp. 1617-1624.
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