Moxifloxacin but not ciprofloxacin or azithromycin selectively inhibits IL-8, IL-6, ERK1/2, JNK, and NF-κB activation in a cystic fibrosis epithelial cell line

Abstract

Cystic fibrosis (CF) is associated with severe neutrophilic airway inflammation. We showed that moxifloxacin (MXF) inhibits IL-8 and MAPK activation in monocytic and respiratory epithelial cells. Azithromycin (AZM) and ciprofloxacin (CIP) are used clinically in CF. Thus we now examined effects of MXF, CIP, and AZM directly on CF cells. IB3, a CF bronchial cell line, and corrected C38 cells were treated with TNF-α, IL-1β, or LPS with or without 5–50 μg/ml MXF, CIP, or AZM. IL-6 and IL-8 secretion (ELISA), MAPKs ERK1/2, JNK, p38, and p65 NF-κB (Western blot) activation were measured. Baseline IL-6 was sixfold higher in IB3 than C38 cells but IL-8 was similar. TNF-α and IL-1β increased IL-6 and IL-8 12- to 67-fold with higher levels in IB3 than C38 cells post-TNF-α ( P < 0.05). Levels were unchanged following LPS. Baseline phosphorylated form of ERK1/2 (p-ERK1/2), JNK, and NF-κB p65 were higher in IB3 than C38 cells (5-, 1.4-, and 1.4-fold), and following TNF-α increased, as did the p-p38, by 1.6- to 2-fold. MXF (5–50 μg/ml) and CIP (50 μg/ml), but not AZM, suppressed IL-6 and IL-8 secretion by up to 69%. MXF inhibited TNF-α-stimulated MAPKs ERK1/2, 46-kDa JNK, and NF-κB up to 60%, 40%, and 40%, respectively. In contrast, MXF did not inhibit p38 activation, implying a highly selective pretranslational effect. In conclusion, TNF-α and IL-1β induce an exaggerated inflammatory response in CF airway cells, inhibited by MXF more than by CIP or AZM. Clinical trials are recommended to assess efficacy in CF and other chronic lung diseases.

Bile Acids Repress Hypoxia-Inducible Factor 1 Signaling and Modulate the Airway Immune Response

“…7A and data not shown) or HIF-1␣ protein levels (Fig. 7B) in IB3-1 cells, which is supported by the observations made in a previous study (44). Moreover, PAO1 LPS and serotype 10 LPS showed distinct profiles (data not shown).…”

A signalome screening approach in the autoinflammatory disease TNF receptor associated periodic syndrome (TRAPS) highlights the anti-inflammatory properties of drugs for repurposing

“…Certain fluoroquinolone derivatives have been reported to selectively inhibit PI3Kg [50]; however, lomefloxacin appears to have broader effects on a number of proinflammatory signalling pathways. The findings reported here do, however, provide a mechanistic basis for the independent, empirical observation of the anti-inflammatory therapeutic benefit of moxifloxacin in a TRAPS patient [36], and concurs with other reports of inhibitory effects of moxifloxacin on MAP-kinases and NFkB [47][48][49]. However, it cannot be excluded that the beneficial effects of moxifloxacin in this patient were due to its anti-microbial activity against infections that might otherwise have triggered TRAPS-associated inflammation; furthermore, moxifloxacin and ciprofloxacin were not beneficial in three other TRAPS patients with the C33Y-TNFR1 mutation [36].…”

“…In particular, with regard to the effects of fluoroquinolones on pro-inflammatory signaling intermediates, it has been reported that norfloxacin and gemifloxacin reduce NFkB expression and activation [43][44][45], and that garenoxacin inhibits Erk1/2 phosphorylation [46]. Moxifloxacin also inhibits Erk1/2, JNK and NFkB [47][48][49]. Certain derivatives of fluoroquinolones have been reported selectively to inhibit PI3Kg [50].…”

Azithromycin Suppresses Activation of Nuclear Factor-kappa B and Synthesis of Pro-inflammatory Cytokines in Tracheal Aspirate Cells From Premature Infants

“…anism of NF-B inhibition by AZM is unknown but there are conflicting reports demonstrating the IB kinase-dependent and independent mechanisms for inhibition of NF-B activation by macrolide antibiotics (24,29,30). Moreover, our own data showed that the TNF-␣-induced IB-␣ degradation (which occurs mainly via IB kinase beta or IKK2-dependent mechanism) is blocked by AZM in TA cells, thereby suggesting that the AZM inhibited NF-B activation by IB-␣ degradation.…”