Interleukin 6 (IL6)

[Mike Bartolatz]

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Interleukin 6
Pamela Bean, Ph.D., MBA, Stacey B. Weston, Ph.D & Janet Cook, M.S., MT(ASCP).


Interleukin 6 (IL-6), originally identified as a B-cell stimulator factor-2 (BSF-2), is a pleiotropic cytokine that acts not only on B cells but also on T cells, hepatocytes, hematopoietic progenitor cells and neuronal cells.1 IL-6 is important in acute phase reactions and is expressed by a variety of normal and transformed cells including T cells, B cells, monocytes/macrophages, fibroblasts, hepatocytes, keratinocytes, astrocytes, vascular endothelial cells, mesangial cells, osteoblasts, Sertoli cells, carcinomas, sarcomas, myelomas, glioblastomas and melanomas.1-3 The pleiotropic functions of IL-6 are summarized below (Table).1 IL-6 is associated with hyperglobulinemia and autoantibody production when secreted by cardiac myxomas or cervical carcinomas.4 IL-6 is elevated post-operatively5 in infection/community-acquired pneumonia,6,7 in alcoholic hepatitis8 and in chronic renal failure.9 IL-6 also appears to be a predominant stimulator for production of acute phase proteins.10

In endotoxin-induced uveitis in rats, which is a model for the uveitis of seronegative spondylarthritis, aqueous-human level of IL-6 was ten-fold than seen in serum suggesting intraocular synthesis of IL-6.11 IL-6 is increased in serum of children with Still disease, in synovial fluid and sometimes in serum in rheumatoid arthritis (RA), in CSF of patients with bacterial meningitis as well as in CNS-lupus, in paraneoplastic syndrome (occasionally found with pheochromocytoma) and in Castleman disease/POEMS.12-19 In RA, as well as in multiple myeloma, there is no useful correlation between IL-6 concentrations and prognosis/diagnosis during treatment regimes.14,15,20,21 IL-6 concentrations are higher in SLE patients compared to RA patients,22 but in some SLE patients, lower IL-6 concentrations may be due to the presence of IL-6 antibodies and soluble IL-6 receptor.23 IL-6 is a co-stimulus for Con A activation of purified T cells.24 IL-6 is also detected in urine from patients with a variety of renal lesions,25 and is increased in patients with nephropathia epidemia; a European form of hantavirus-induced hemorrhagic fever with renal syndrome.26 Release of IL-6 by normal and neoplastic B cells and by cells derived from AIDS Kaposi sarcomas27 is expected to have important effects on cells in their microenvironment.28 Serum IL-6 concentrations correlate with disease severity in plasma cell dyscrasias29 and also in Hodgkin disease.30 Plasma (EDTA and aprotinin) is probably more appropriate for study than serum.31 IL-6 is increased in plasma and on dermal and epidermal cells in lesional skin of psoriasis.32 Increases of serum IL-6 are found in Castleman disease,33 in which inappropriate synthesis of IL-6 probably has a primary role in pathogenesis.34 IL-6 is increased in CSF in (50% of HTLV-I-associated myelopathy and in about 80% (12/15) of amyotrophic lateral sclerosis.35 Treatment with antibodies to IL-6 prevents the hypergammaglobulinemia of experimental cerebral malaria.36 Increased post-menopausal osteoclast development is stimulated by IL-6 and inhibited by estrogens,37 plasma IL-6 concentrations are elevated in post-menopausal women.38

Substantial in vitro evidence indicates that IL-6 contributes to the pathogenesis of Kaposi sarcoma (KS), an angioproliferative inflammatory condition that occurs commonly in patients infected with HIV.39 Inflammatory cytokines and growth factors promote the development of KS. A recent report suggests that IL-6 promoter genotypes associated with altered gene expression are risk factors for development of KS;40 identification of such a genetic risk factor has important clinical implications for prevention and therapy. IL-6 also interacts with several factors which are involved in the pathogenesis of multiple myeloma such as adhesion molecules, tumour suppressor genes and oncogenes.41 IL-6 could serve as a target for new therapeutic interventions since neutralizing the effect of IL-6 may result in tumor regression. In recurrent breast cancer, IL-6 and IL-8 levels at the beginning of treatment are predictive indicators of response to therapy and prognosis; continuous elevation of IL-6 levels indicates poor prognosis in heavily pretreated patients. 42 Combination therapy including agents that reduce IL-6 levels will become a new strategy for aggressively treating recurrent breast cancer.42

A recent report concludes that circulating levels of IL-6 and TNFalpha are increased in type 2 diabetes but there is downregulation of basal cytokine production in blood cells derived from these patients. Blood has the capacity to produce cytokines in diabetes which contribute to the augmented acute-phase response, but the main source of the increased plasma IL-6 and TNFalpha concentrations may be from non-circulating cells.43

Since plasma levels of IL-6 and IL-6Rs were significantly increased in 28 patients with acute myocardial infarction compared with 15 normal controls, a recent study suggests that IL-6 with its proinflammatory role, plays a key role in the pathogenesis of coronary artery disease (CAD).44 The amount of IL-6 produced is closely related to the severity of myocardial dysfunction. IL-6 is a strong independent marker of increased risk for mortality in patients with unstable CAD, and while patients with high plasma levels of IL-6 have the highest mortality rates, they also benefit most from a strategy of early revascularization.45,46

IL-6 in umbilical cord blood seems to be a promising predictor for early-onset neonatal infections.47 IL6 activates the hypothalamic-pituitary-adrenal axis and may have a pathological role in aging and chronic stress.48


Table: Pleiotropic Effects of IL-6

Modified from Kishimoto T, et al. Blood 1995;86:1243-54.

B cells
Ig production

Proliferation of myeloma cells

Proliferation of Epstein-Barr virus-infected B cells

T cells
Proliferation and differentiation of T cells

Differentiation of cytotoxic T lymphocytes

Induction of IL-2R expression and IL-2 production

Augmentation of NK activities

Hematopoietic progenitor cells
Enhancement of multipotential hematopoietic colony formation

Megakaryocytes
Megakaryocyte maturation

Macrophages
Growth inhibition of myeloid leukemic cells lines and induction of their macrophage differentiation

Hepatocytes
Acute-phase protein synthesis

Bone metabolism
Stimulation of osteoclast formation

Induction of bone resorption

Blood vessels
Induction of platelet-derived growth factor

Proliferation of vascular smooth muscle cells

Heart muscle cells
Negative inotropic effect on heart

Neuronal cells
Neural differentiation of PC12 cells

Support of survival of cholinergic neurons

Induction of adrenocorticotropic hormone synthesis

Placenta
Secretion of chorionic gonadotropin from trophoblasts





Relevant Tests Offered by Specialty
7584C Epstein-Barr Virus DNA UltraRapid® CSF
3828 Interleukin-6
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REFERENCES


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