Smooth muscle cells in the tunica media of many blood vessels also produce IL-6 as a pro-inflammatory cytokine.

There is some early evidence that IL-6 can be used as an inflammatory marker for severe COVID-19 infection with poor prognosis, in the context of the wider coronavirus pandemic.

[6] IL-6 is secreted by macrophages in response to specific microbial molecules, referred to as pathogen-associated molecular patterns (PAMPs).

It is capable of crossing the blood–brain barrier[7] and initiating synthesis of PGE2 in the hypothalamus, thereby changing the body's temperature setpoint.

[17] Studies in experimental animals indicate that IL-6 in the CNS partly mediates the suppression of food intake and body weight exerted by glucagon-like peptide-1 (GLP-1) receptor stimulation.

[9] It has been shown that the reduction of abdominal obesity by exercise in human adults can be reversed by the IL-6 receptor blocking antibody tocilizumab.

The exercise-induced increase of plasma IL-6 occurs in an exponential manner and the peak IL-6 level is reached at the end of the exercise or shortly thereafter.

As a matter of fact, eccentric exercise may result in a delayed peak and a much slower decrease of plasma IL-6 during recovery.

[34] Recent work has shown that both upstream and downstream signalling pathways for IL-6 differ markedly between myocytes and macrophages.

[37] IL-6 signals through a cell-surface type I cytokine receptor complex consisting of the ligand-binding IL-6Rα chain (CD126), and the signal-transducing component gp130 (also called CD130).

The sIL-6R/IL-6 complex can stimulate neurites outgrowth and promote survival of neurons and, hence, may be important in nerve regeneration through remyelination.

[45] There is considerable functional overlap and interaction between Substance P (SP), the natural ligand for the neurokinin type 1 receptor (NK1R, a mediator of immunomodulatory activity) and IL-6.

[63] It has been observed that genetic inactivation of ZCCHC 6 suppresses IL‐6 expression and reduces the severity of experimental osteoarthritis in Mice.

[64] Some plant derived small molecule such as Butein have been reported to inhibit IL-6 expression in IL-1β stimulated human chondrocytes.

[67][68][69][70][71] In patients with severe alcohol-associated hepatitis, IL-6 showed the most robust elevation among inflammatory cytokines compared to healthy controls with a further increase in non-survivors.

[80] High IL-6 levels are associated with the development of encephalitis in children and immunodeficient mouse models infected with Enterovirus 71; this highly contagious virus normally causes a milder illness called Hand, foot, and mouth disease but can cause life-threatening encephalitis in some cases.

[87] IL-6 is commonly found in the senescence-associated secretory phenotype (SASP) factors secreted by senescent cells (a toxic cell-type that increases with aging).

[88][89] Cancer (a disease that increases with age) invasiveness is promoted primarily though the actions of the SASP factors metalloproteinase, chemokine, IL-6, and interleukin 8 (IL-8).

Depression is marked by altered connectivity, in particular between the anterior cingulate cortex and several other limbic areas, such as the hippocampus.

[92] Additional preclinical and clinical data, suggest that Substance P [SP] and IL-6 may act in concert to promote major depression.

SP, a hybrid neurotransmitter-cytokine, is co-transmitted with BDNF through paleo-spinothalamic circuitry from the periphery with collaterals into key areas of the limbic system.

[97] This is of key interest as: 1) a meta-analysis indicates an association of major depressive disorder, C-reactive protein and IL6 plasma concentrations,[98] 2) NK1R antagonists [five molecules] studied by 3 independent groups in over 2000 patients from 1998 to 2013 validate the mechanism as dose-related, fully effective antidepressant, with a unique safety profile.

[102] These and many other reports suggest that a clinical study of a neutralizing IL-6 biological or drug based antagonist is likely warranted in patients with major depressive disorder, with or without co-morbid chronic inflammatory based illnesses; that the combination of NK1RAs and IL6 blockers may represent a new, potentially biomarkable approach to major depression, and possibly bipolar disorder.

The IL-6 antibody sirukumab underwent clinical trials for adjunctive treatment of major depressive disorder in 2015–2018,[103] but this research has been discontinued.

Recent data suggests that the inflammation associated with obesity, potentially mediated by IL-6, plays a role in causing poor lung function and increased risk for developing asthma exacerbations.