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LPS induced TH2 (Interleukin-4) cytokine production in macrophages and its regulation

Mukherjee, Sumanta

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2008, Doctor of Philosophy in Medical Sciences (Ph.D.), University of Toledo, College of Graduate Studies.

Gram negative LPS signaling through TLR4 is a potent inducer of the innate immune system and also directs the adaptive immune response. LPS activation of macrophages induces various Th1 type cytokines like TNF-α, IFN-γ and IL-12. Although some recent studies reported human alveolar macrophages as potential sources for Th2 cytokines, little however is known about the intracellular events that lead to LPS induced Th2 cytokine production. Also deregulated Th2 cytokine production is often associated with potentially deleterious immune responses such as septic shock or exacerbation of asthma. It therefore necessitates proper understanding of the regulation of LPS inducedcytokine production. This study therefore examined the role of LPS in IL-4 (hallmark of Th2 cytokines) production by macrophages and its regulation. It was observed that low dose of LPS induced early TNF-α and delayed IL-4 gene expression in various types of murine macrophages in vitro. LPS induced IL-4 production was TLR4 dependent, transcriptionally regulated and required de novo protein synthesis. Moreover IL-4 production was both MyD88 dependent and independent whereas TNF-α was only MyD88 dependent. Downstream adaptor molecules IRAK-1 and TRAF-6 and transcription factors NF-κB and IRF-3 also positively regulated IL-4 production in macrophages.

CYLD a deubiquitinase was recently reported to be a negative regulator of TLR2 signaling induced NF-κB activation via negative cross talk with TRAF6 and TRAF7. However the role of CYLD in LPS-TLR4 signaling, specifically in IL-4 production in macrophages is yet to be determined. In this study we provide evidence that CYLD negatively regulates LPS induced IL4 but not TNF-α. Our data demonstrates for the first time that LPS induces CYLD in a TLR4, MyD88 and NF-κB dependent manner and this induction of CYLD is crucial in negatively regulating IL-4 production in macrophages. Our data suggest that CYLD interacts with MyD88 endogenously. The interaction attenuated the functional activity of MyD88 resulting in an inhibition of activation of IRAK-1. IRAK-1 inactivation in turn inhibited the phosphorylation of IκBα and thereby blocked NF-κB. NF-κB inactivation inhibited IL-4 production. The findings probe into the possible initial inhibition of LPS induced IL-4 production in macrophages and identifies a novel mechanism of CYLD action.

Z. Kevin Pan, PhD (Committee Chair)
Thomas Papadimos, MD (Committee Member)
Han-Fei Ding, PhD (Committee Member)
William Maltese, PhD (Committee Member)
R. Mark Wooten, PhD (Committee Member)
Lingyu Chen, PhD (Committee Member)
186 p.

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Citations

  • Mukherjee, S. (2008). LPS induced TH2 (Interleukin-4) cytokine production in macrophages and its regulation [Doctoral dissertation, University of Toledo]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=mco1207743729

    APA Style (7th edition)

  • Mukherjee, Sumanta. LPS induced TH2 (Interleukin-4) cytokine production in macrophages and its regulation. 2008. University of Toledo, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=mco1207743729.

    MLA Style (8th edition)

  • Mukherjee, Sumanta. "LPS induced TH2 (Interleukin-4) cytokine production in macrophages and its regulation." Doctoral dissertation, University of Toledo, 2008. http://rave.ohiolink.edu/etdc/view?acc_num=mco1207743729

    Chicago Manual of Style (17th edition)