A Role for IFITM Proteins in Restriction of Mycobacterium tuberculosis Infection

Ranjbar, Shahin; Haridas, Viraga; Jasenosky, Luke D.; Falvo, James V.; Goldfeld, Anne E.

Although MTb induces the expression of type I IFN (Berry et al., 2013) , the prototypical stimulus of IFITM gene expression, MTb also induces the expression of other proinflammatory cytokines that are critical mediators of the host innate immune response, including IL-1β, IL-6, and TNF (Etna et al., 2014) . Direct activation of the MTb-responsive PRRs TLR2 and TLR4 on THP-1 cells led to significantly enhanced levels of IL-1β, TNF, and IL-6 mRNA by 24 hr ( Figure S2 ). While IL-1β signaling requires the MyD88/IRAK1/ TRAF6 axis, TNF and IL-6 activate distinct signaling pathways (Falvo et al., 2011) . To investigate if these cytokines directly induce IFITM gene expression in monocytic cells, we treated THP-1 cells with recombinant IL-1β, IL-6, or TNF, or, as a positive control, recombinant IFN-β, and assessed IFITM1-3 transcript levels. As anticipated, IFN-β stimulation dramatically induced IFITM1-3 transcription ( Figure 1E ). By 24 hr poststimulation, both IL-1β and TNF also significantly upregulated IFITM1 gene expression, and all three cytokines significantly increased IFITM3 mRNA levels. At 48 hr, IFITM1 mRNA synthesis also was increased significantly by IL-6, and IFITM2 transcription was enhanced significantly at this time point by both IL-6 and TNF ( Figure 1E ). Taken together, these data indicate that IFITM1-3 gene expression is induced by secondary signaling pathways, including those triggered by binding of IL-1β, IL-6, and TNF to their cognate receptors, activated during MTb infection in addition to being directly activated by MTb and MyD88-dependent TLR ligation.