Interleukins (IL) are immunomodulatory proteins that elicit a wide array of responses in cells and tissues. Interleukin 37 (IL 37), also known as IL 1F7, is a member of the IL 1 family. There are five isoforms of IL 37 (a e) of which transcript IL 37b is known to be functional (Sharma S et al., 2008). Like several other IL 1 family members, IL 37b is synthesized as precursors that require processing (primarily by caspase 1) to attain full receptor agonist or antagonist function (Kumar S et al., 2002). Mothers against decapentaplegic homolog 3 (SMAD3) binds SMAD4 and this complex modulates the transcription of several genes downstream. Processed IL 37b can bind with phosphorylated SMAD3 in the cytosol of A549 cells (Nold M F et al., 2010, Grimsby S et al., 2004). This complex may then translocate from the cytosol to the nucleus (Nold M F et al., 2010, Dinarello et al. 2016) and may affect the function of SMAD3. These events ultimately lead to suppression of cytokine production in several types of immune cells resulting in reduced inflammation. This is a black box event because SMAD3 assisted IL-37 translocation to the nucleus is not fully understood.