Interleukin-6 (IL-6) is a pro-inflammatory cytokine secreted by T cells and macrophages to stimulate immune response to trauma, especially burns or other tissue damage leading to inflammation. Additionally osteoblasts to stimulate osteoclast formation. Inhibitors of IL-6 (including estrogen) are used to treat postmenopausal osteoporosis. IL-6 is one of the most important mediators of fever and of the acute phase response. In the muscle and fatty tissue IL-6 stimulates energy mobilization which leads to increased body temperature. IL-6 can be secreted by macrophages in response to pathogen associated molecular patterns (PAMPs) binding the Toll-like Receptor (TLR) present on an active macrophage.
IL-6 is released in response to IL-1 and TNF-b () The IL-6 receptor is found on many cell surfaces, including resting normal T-cells, activated normal B-cells, myeloid cell lines, hepatoma cell lines, myeloma cell lines, and on Epstein-Barr virus (EBV) modified B-cells, in which it promotes proliferation. ()
Recently, it has been shown that IL-6 also acts as a "myokine," a cytokine produced from muscle, and is elevated in response to muscle contraction ().
Suggested pathway of interaction leading to Secreted of IL-6 and some of its possible effects. Source
IL-6 mediates its responses through cell surface receptors that include the transmambrane protein gp130. IL-6 triggers the formation of protein complexes of gp130 and the IL-6 receptor activating the receptor. These complexes bring together the intracellular regions of gp130 and initiates the signal transduction cascade through Janus kinases (JAKs) and Signal Transducers and Activators of transcription (STATs).
IL-6 is probably the best studied of the cytokines that utilise gp130 in their signalling complexes. Other cytokines that signal through receptors containing gp130 are Interleukin-11 (IL-11), ciliary neurotrophic factor (CNTF), cardiotrophin-1 (CT-1), cardiotrophin-like cytokine (CLC), leukemia inhibitory factor (LIF), oncostatin M (OSM), Kaposi's sarcoma associated herpes virus interleukin 6 like protein (KSHV-IL6). These cytokines are comonly referred to as the IL-6 like or gp130 utilising cytokines.
Drugs that Bind IL-6
Because IL-6 plays a major role in many undesired effects of the immune system, some research has been done into preventing its binding. However, it has been found somewhat more effective to bind IL-1 and TNF-b , and in this way reduce the secretion of IL-6 in the first place. One important drug in this field is the anti IL- 6 receptor antibody (MRA), used as one of new therapeutic approaches in rheumatic arthritis.
Pathology of fatal human infection associated with avian influenza A H5N1 virus
J Med Virol. 2001 Mar;63(3):242-6
To KF, Chan PK, Chan KF, Lee WK, Lam WY, Wong KF, Tang NL, Tsang DN, Sung RY, Buckley TA, Tam JS, Cheng AF.
- Eighteen cases of human influenza A H5N1 infection were identified in Hong Kong from May to December 1997. Two of the six fatal cases had undergone a full post-mortem which showed reactive hemophagocytic syndrome as the most prominent feature. Other findings included organizing diffuse alveolar damage with interstitial fibrosis, extensive hepatic central lobular necrosis, acute renal tubular necrosis and lymphoid depletion. Elevation of soluble interleukin-2 receptor, interleukin-6 and interferon-gamma was demonstrated in both patients, whereas secondary bacterial pneumonia was not observed. Virus detection using isolation, reverse transcription-polymerase chain reaction and immunostaining were all negative. It is postulated that in fatal human infections with this avian subtype, initial virus replication in the respiratory tract triggers hypercytokinemia complicated by the reactive hemophagocytic syndrome. These findings suggest that the pathogenesis of influenza A H5N1 infection might be different from that of the usual human subtypes H1-H3.
The inhibitory effect of quercetin on IL-6 production by LPS-stimulated neutrophils
Cell Mol Immunol. 2005 Dec;2(6):455-60. Liu J, Li X, Yue Y, Li J, He T, He Y.
- Quercetin is a herbal flavonoid derived from various foods of plant origin and plays a role in anti-inflammation. Although a number of researches in the field have been done, the mechanism of anti-inflammatory effect of quercetin should be further clarified. In the present study, we investigated the effects of quercetin on IL-6 production by LPS-stimulated neutrophils in human. Neutrophils were were pre-treated with quercetin at the final concentrations of ranging from 0-80 microM for 30 min, or not treated, and then incubated in the presence or absence of lipopolysaccharide (LPS) at a final concentration of 100 ng/ml for indicated time. The secretion level of IL-6 in the culture supernatants was assayed by ELISA, the intracellular level of IL-6 was detected by flow cytometry and the expression of IL-6 mRNA was analyzed by RT-PCR. The experiment results showed that neutrophils cultured with medium or quercetin alone did not express IL-6, but LPS (100 ng/ml) induced IL-6 expression of neutrophils. However, after pre-treatment of neutrophils with quercetin (40 microM) for 30 min, the inducible effects of LPS on the increase of IL-6 secretion, intracellular IL-6 level and IL-6 mRNA expression by neutrophils were abrogated. IL-6 is one of the important pro-inflammatory factors, especially in early phage of inflammation. Thus, our data suggested that quercetin might exert its anti-inflammatory effect through negatively modulating pro-inflammatory factors, such as IL-6. The inhibitory effects of quercetin on IL-6 production by neutrophils may provide a theoretical basis on future therapy of inflammation.
Tanshinone IIA from Salvia miltiorrhiza inhibits inducible NO synthase, TNF-alpha, IL-1beta and IL-6
Planta Med. 2003 Nov;69(11):1057-9. Jang SI, Jeong SI, Kim KJ, Kim HJ, Yu HH, Park R, Kim HM, You YO.
The inhibitory effects of tanshinone IIA, a diterpene isolated from Salvia miltiorrhiza root, on the production of nitric oxide (NO), interleukin-1beta (IL-1beta), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha), and the expression of inducible nitric oxide synthase (iNOS) were investigated in activated RAW 264.7 cells. This compound markedly inhibited the production of NO, IL-1beta and TNF-alpha, and suppressed the expression of iNOS in a dose-dependent manner. These results suggest that the traditional use of S. miltiorrhiza as an anti-inflammatory herbal medicine may be explained, in part, by the inhibition of NO, IL-1beta, IL-6 and TNF-alpha production, and expression of iNOS.