Selective Inhibitors of Janus Kinase 3 Modify Responses to Lipopolysaccharides by Increasing the Interleukin-10-to-Tumor Necrosis Factor α Ratio

Julian Laux; Mariella Martorelli; Nadja Späth; Florian Maier; Michael Burnet; Stefan A Laufer

doi:10.1021/acsptsci.3c00043

Selective Inhibitors of Janus Kinase 3 Modify Responses to Lipopolysaccharides by Increasing the Interleukin-10-to-Tumor Necrosis Factor α Ratio

ACS Pharmacol Transl Sci. 2023 May 18;6(6):892-906. doi: 10.1021/acsptsci.3c00043. eCollection 2023 Jun 9.

Authors

Julian Laux^{1

2}, Mariella Martorelli^{1

2}, Nadja Späth¹, Florian Maier¹, Michael Burnet¹, Stefan A Laufer^{2

3

4}

Affiliations

¹ Synovo GmbH, Paul-Ehrlich-Straße 15, 72076 Tübingen, DE, Germany.
² Department of Pharmaceutical/Medicinal Chemistry, Eberhard Karls University Tübingen, Auf der Morgenstelle 8, 72076 Tübingen, DE, Germany.
³ Cluster of Excellence iFIT (EXC 2180) "Image-Guided and Functionally Instructed Tumor Therapies", University of Tübingen, 72076 Tübingen, Germany.
⁴ Tübingen Center for Academic Drug Discovery & Development (TüCAD2), 72076 Tübingen, Germany.

Abstract

Janus kinase (JAK) inhibitors act at low doses (e.g., tofacitinib, 0.2-0.4 μmol/kg bid) in clinical use, suggesting an efficient underlying mode of action. We hypothesized that their effectiveness is due to their ability to raise the ratio of IL-10 to TNFα. Unlike other JAK isoforms, JAK3 is expressed mainly in hematopoietic cells and is essential for immune function. We used JAK3 selective inhibitors with preferential distribution to immune cells. Inhibition of JAK3 in human leukocytes reduced TNFα and IL-6 but maintained levels of IL-10, while pan-JAK inhibitors increased TNFα, IL-6, and IL-10. JAK1 is required for IL-10 receptor signaling, which suggests that, at exposure above the IC₅₀ (55 nM for tofacitinib on JAK1), there is less feedback control of TNFα levels. This leads to self-limiting effects of JAK1 inhibitors and could place an upper limit on appropriate doses. In vivo, treating mice with JAK3 inhibitors before LPS administration decreased plasma TNFα and increased IL-10 above vehicle levels, suggesting that JAK3 inhibition may limit TNFα release by increasing IL-10 while leaving the IL-10 receptor functional. This mechanism should have general utility in controlling autoimmune diseases and can be conveniently observed by measuring the ratio of IL-10 to TNFα. In summary, our targeted, "leukotropic" inhibitors more effectively increased IL-10/TNFα ratios than unselective control compounds and could, therefore, be ideal for autoimmune therapy.