systemic reaction characterized by fever, leukocytosis, increase in erythrocyte sedimentation rate, increases in Leucocytosis secretion of ACTH and glucocorticoids, activation of Complement activat complement and clotting cascades, decreases in serum levels of iron and zinc, a negative nitrogen balance, and by dramatic changes in the concentration of some plasma ,l' proteins. These proteins are named acute phase proteins. i

Interleukin-6 and the acute phase response

Interleukin 6 (IL-6), promptly and transiently produced in response to infections and tissue injuries, contributes to host defense through the stimulation of acute phase responses, hematopoiesis, and immune reactions. Although its expression is strictly controlled by transcriptional and posttranscriptional mechanisms, dysregulated continual synthesis of IL-6 plays a pathological effect on chronic inflammation and autoimmunity. For this reason, tocilizumab, a humanized anti-IL-6 receptor antibody was developed. Various clinical trials have since shown the exceptional efficacy of tocilizumab, which resulted in its approval for the treatment of rheumatoid arthritis and juvenile idiopathic arthritis. Moreover, tocilizumab is expected to be effective for other intractable immune-mediated diseases. In this context, the mechanism for the continual synthesis of IL-6 needs to be elucidated to facilitate the development of more specific therapeutic approaches and analysis of the pathogenesis of specific diseases.

/pdf/il-6-in-inflammation-immunity-and-disease-4vb9xupl1q.pdf

IL-6 in Inflammation, Immunity, and Disease

The biology of interleukin-6.

Interleukin-6: An Overview

Hematopoietic progenitor cells migrate in vitro and in vivo towards a gradient of the chemotactic factor stromal cell-derived factor-1 (SDF-1) produced by stromal cells. This is the first chemoattractant reported for human CD34+ progenitor cells. Concentrations of SDF-1 that elicit chemotaxis also induce a transient elevation of cytoplasmic calcium in CD34+ cells. SDF-1-induced chemotaxis is inhibited by pertussis toxin, suggesting that its signaling in CD34+ cells is mediated by seven transmembrane receptors coupled to Gi proteins. CD34+ cells migrating to SDF-1 include cells with a more primitive (CD34+/CD38- or CD34+/DR-) phenotype as well as CD34+ cells phenotypically committed to the erythroid, lymphoid and myeloid lineages, including functional BFU-E, CFU-GM, and CFU-MIX progenitors. Chemotaxis of CD34+ cells in response to SDF-1 is increased by IL-3 in vitro and is lower in CD34+ progenitors from peripheral blood than in CD34+ progenitors from bone marrow, suggesting that an altered response to SDF-1 may be associated with CD34 progenitor mobilization.

/pdf/the-chemokine-sdf-1-is-a-chemoattractant-for-human-cd34-unn9nzvgta.pdf

The Chemokine SDF-1 Is a Chemoattractant for Human CD34+ Hematopoietic Progenitor Cells and Provides a New Mechanism to Explain the Mobilization of CD34+ Progenitors to Peripheral Blood

Interleukin-6 is a potent thrombopoietic factor in vivo in mice.

A series of combretastatin A-4 (CA-4) analogues were synthesized, and their cytotoxic effects against murine Colon 26 adenocarcinoma and inhibitory activity on tubulin polymerization were evaluated. Since CA-4 has limited aqueous solubility, the target compounds were designed to improve solubility by introduction of a nitrogen-containing group. Among the compounds synthesized, those with an amino moiety in place of the phenolic OH of CA-4 showed potent antitubulin activity and cytotoxicity against murine Colon 26 adenocarcinoma in vitro. Some of the compounds which were potent in vitro were evaluated in the murine tumor model Colon 26 in vivo. Among these, 13bHCl, 21aHCl, and 21bHCl showed significant antitumor activity in the animal model, while CA-4 was ineffective. 13bHCl and 21aHCl were further evaluated in two murine tumor models (Colon 38 and 3LL) and human xenografts HCT-15. These compounds showed potent antitumor activity comparable or superior to that of CDDP. The structure−activity relationships...

Novel Combretastatin Analogues Effective against Murine Solid Tumors: Design and Structure−Activity Relationships

Syntheses and antitumor activity of cis-restricted combretastatins: 5-Membered heterocyclic analogues

https://febs.onlinelibrary.wiley.com/doi/pdf/10.1016/0014-5793%2888%2981293-6

Recombinant human interleukin 6 (B-cell stimulatory factor 2) is a potent inducer of differentiation of mouse myeloid leukemia cells (M1).

The effects of human rIL-6/B cell stimulatory factor 2 (hrIL-6/BSF-2) from Escherichia coli on murine Ag, SRBC-specific antibody responses were examined in vitro and in vivo. HrBSF-2 was effective in augmenting the primary and the anamnestic plaque-forming cells response to SRBC in vitro. The augmentation of the primary response was apparent when B cell-enriched spleen cells (B cells) were cultured with BSF-2 in the presence of IL-2. On the other hand, hrBSF-2 alone strongly enhanced the anamnestic response in a dose-dependent manner when spleen cells from SRBC-immunized mice were used. These effects of BSF-2 were abolished completely by anti-BSF-2 antibody, but not by normal rabbit Ig. Cell depletion experiments indicated that L3T4 (CD4)+ T cells, but not Lyt-2(CD8)+ T cells, and adherent cells (macrophages) have an important role in this BSF-2-induced augmentation of the response. In addition, kinetic studies showed that hrBSF-2 acts on B cells in the anamnestic response even when added relatively late in the culture. Finally, it was determined whether BSF-2 also could be active in modulating antibody responses in vivo. BSF-2 was shown to enhance the primary and secondary antibody responses in mice. The most apparent effect of BSF-2 was observed in the secondary response.

Yukio Akiyama

Papers

Interleukin-6 is a potent thrombopoietic factor in vivo in mice.

Novel Combretastatin Analogues Effective against Murine Solid Tumors: Design and Structure−Activity Relationships

Syntheses and antitumor activity of cis-restricted combretastatins: 5-Membered heterocyclic analogues

Recombinant human interleukin 6 (B-cell stimulatory factor 2) is a potent inducer of differentiation of mouse myeloid leukemia cells (M1).

Human recombinant IL-6/B cell stimulatory factor 2 augments murine antigen-specific antibody responses in vitro and in vivo.