From the authors
We thank Drs. Garbers and Rose-John for their interest in our study, where we found that a loss-of-function polymorphism in the interleukin-6 receptor (IL6R) gene reduces risk of the JAK2V617F somatic mutation and myeloproliferative neoplasm [1]. They raise some interesting points related to the underlying mechanism of soluble IL6R (sIL6R) and its relationship with tocilizumab treatment, a monoclonal antibody that targets the IL6R [2].
We used the genetic polymorphism rs4537545 that is in high linkage disequilibrium with rs2228145 in the IL6R gene, which causes the non-synonymous exchange of Asp-358 to Ala-358 in the IL6R protein. This results in reduced membrane-bound IL6R due to increased proteolytic cleavage followed by increased sIL6R concentration [1,3]. This blocks the classical signalling pathway of IL6R and thereby dampens inflammation. Indeed, as emphasized by Garbers and Rose-John, increased sIL6R in combination with soluble glycoprotein-130 in the blood circulation can act as a natural buffer that can neutralize IL6, thereby also dampen inflammation [1,4,5].
We agree that tocilizumab treatment, with reservations to its pharmacokinetic properties, will potentially block all sIL6R molecules thereby rendering them biologically inactive. In contrast, sIL6R molecules in individuals with genetic polymorphism in IL6R are fully biologically active. Although the two scenarios may not be fully comparable, it does not change the notion that treatment with tocilizumab and other agents that target the same inflammatory pathway such as canakinumab, a monoclonal antibody that targets the more central regulator interleukin-1β, could potentially be considered as candidate drugs for myeloproliferative neoplasms.
Declaration of Competing Interests
KMP reports grants from the Danish Karen Elise Jensen Foundation during the conduct of this work. YÇ reports grants from the Lundbeck Foundation and personal fees from Boehringer Ingelheim, AstraZeneca, and Sanofi Genzyme outside the submitted work. HCH reports grants from Novartis Denmark and personal fees from AOP Orphan Pharmaceuticals AG and PharmaEssentia outside the submitted work. SEB and BGN have nothing to disclose in relation to this work.
Role of the funding source
This work was funded by the Danish Karen Elise Jensen Foundation. YÇ was funded by the Lundbeck Foundation. The funders had no role in the writing of the manuscript or in the decision to submit for publication. The corresponding author had final responsibility for the decision to submit for publication.
Footnotes
Response to: Soluble interleukin-6 receptor in patients with JAK2V617F somatic mutation and myeloproliferative neoplasm.
References
- 1.Pedersen K.M., Çolak Y., Ellervik C., Hasselbalch H.C., Bojesen S.E., Nordestgaard B.G. Loss-of-function polymorphism in IL6R reduces risk of JAK2V617F somatic mutation and myeloproliferative neoplasm: A Mendelian randomization study. EClinicalMedicine. 2020 doi: 10.1016/j.eclinm.2020.100280. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Garbers C., Rose-John S. Soluble interleukin-6 receptor in patients with JAK2V617F somatic mutation and myeloproliferative neoplasm. EClinicalMedicine. 2020 doi: 10.1016/j.eclinm.2020.100340. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Garbers C., Monhasery N., Aparicio-Siegmund S. The interleukin-6 receptor Asp358Ala single nucleotide polymorphism rs2228145 confers increased proteolytic conversion rates by ADAM proteases. Biochim Biophys Acta. 2014;1842(9):1485–1494. doi: 10.1016/j.bbadis.2014.05.018. [DOI] [PubMed] [Google Scholar]
- 4.Aparicio-Siegmund S., Garbers Y., Flynn C.M. The IL-6-neutralizing sIL-6R-sgp130 buffer system is disturbed in patients with type 2 diabetes. Am J Physiol Endocrinol Metab. 2019;317(2):E411–E420. doi: 10.1152/ajpendo.00166.2019. [DOI] [PubMed] [Google Scholar]
- 5.Garbers C., Heink S., Korn T., Rose-John S. Interleukin-6: designing specific therapeutics for a complex cytokine. Nat Rev Drug Discov. 2018;17(6):395–412. doi: 10.1038/nrd.2018.45. [DOI] [PubMed] [Google Scholar]