Ruxolitinib inhibits cytokine production by human lung macrophages without impairing phagocytic ability

Abstract

Background: The Janus kinase (JAK) 1/2 inhibitor ruxolitinib has been approved in an indication of myelofibrosis and is a candidate for the treatment of a number of inflammatory or autoimmune diseases. We assessed the effects of ruxolitinib on lipopolysaccharide (LPS)- and poly (I:C)-induced cytokine production by human lung macrophages (LMs) and on the LMs’ phagocytic activity.Methods: Human LMs were isolated from patients operated on for lung carcinoma. The LMs were cultured with ruxolitinib (0.5 × 10−7 M to 10–5 M) or budesonide (10–11 to 10–8 M) and then stimulated with LPS (10 ng·ml−1) or poly (I:C) (10 μg·ml−1) for 24 h. Cytokines released by the LMs into the supernatants were measured using ELISAs. The phagocytosis of labelled bioparticles was assessed using flow cytometry.Results: Ruxolitinib inhibited both the LPS- and poly (I:C)-stimulated production of tumor necrosis factor alpha, interleukin (IL)-6, IL-10, chemokines CCL2, and CXCL10 in a concentration-dependent manner. Ruxolitinib also inhibited the poly (I:C)- induced (but not the LPS-induced) production of IL-1ß. Budesonide inhibited cytokine production more strongly than ruxolitinib but failed to mitigate the production of CXCL10. The LMs’ phagocytic activity was not impaired by the highest tested concentration (10–5 M) of ruxolitinib.Conclusion: Clinically relevant concentrations of ruxolitinib inhibited the LPS- and poly (I:C)-stimulated production of cytokines by human LMs but did not impair their phagocytic activity. Overall, ruxolitinib’s anti-inflammatory activities are less intense than (but somewhat different from) those of budesonide—particularly with regard to the production of the corticosteroid-resistant chemokine CXCL-10. Our results indicate that treatment with a JAK inhibitor might be a valuable anti-inflammatory strategy in chronic obstructive pulmonary disease, Th1-high asthma, and both viral and non-viral acute respiratory distress syndromes (including coronavirus disease 2019).

Serum proteomics hint at an early T-cell response and modulation of SARS-CoV-2-related pathogenic pathways in COVID-19-ARDS treated with Ruxolitinib

“…Ruxo has been repurposed for the treatment of SARS-CoV-2 infection in different clinical settings inside and outside of clinical trials, but the clinical significance of this drug in COVID-19 pneumonia and ARDS remains to be firmly established (18,20,21,32,56,(59)(60)(61)(62). The work presented here adds to previous work on the mechanisms of action of Ruxo in hyperinflammation and respiratory distress (63,64). Specifically, we aimed to gain deeper insights into systemic effects of Ruxo in critical COVID-19 by studying serum proteomes by MS and cytokine array analyses at different time points after initiation of treatment.…”