Inflammatory Proliferative Diseases Research Articles

Pigmented Villonodular Synovitis for Combined Therapy

Pigmented villonodular synovitis (PVNS), inflammatory proliferative disease resulting from synovial cells, has progressive course similar neoplastic local expansion. We followed up a case with effective combined therapy for diffuse PVNS despite incomplete response to its components and reviewed therapies based on MedLine for PVNS. Due to US data residue synovitis after open radical synovectomy, we made decision about external beam radiotherapy. Photon radiation with linear accelerator energy of 6 MV was applied for two fields: anterior and posterior. The total dose was 20 Gy, delivered in 2 Gy a day, five times a week. Due to postoperative pain and the rest of synovial tissue on US study, pharmacologic therapy with salazopyrine and celecoxib was added. For several weeks, the knee pain became episodic and further disappeared. Six months later, the patient feels healthy and continues to take salazopyrine permanently and celecoxib as needed. We conclude high rate response analyzing literature data and our case to combined therapy: arthroscopic or open surgery followed by RT along with complimentary pharmacotherapy. J Med Cases. 2014;5(3):147-151 doi: http://dx.doi.org/10.14740/jmc1656e

Pigmented Villonodular Synovitis for Combined Therapy

Pigmented villonodular synovitis (PVNS), inflammatory proliferative disease resulting from synovial cells, has progressive course similar neoplastic local expansion. We followed up a case with effective combined therapy for diffuse PVNS despite incomplete response to its components and reviewed therapies based on MedLine for PVNS. Due to US data residue synovitis after open radical synovectomy, we made decision about external beam radiotherapy. Photon radiation with linear accelerator energy of 6 MV was applied for two fields: anterior and posterior. The total dose was 20 Gy, delivered in 2 Gy a day, five times a week. Due to postoperative pain and the rest of synovial tissue on US study, pharmacologic therapy with salazopyrine and celecoxib was added. For several weeks, the knee pain became episodic and further disappeared. Six months later, the patient feels healthy and continues to take salazopyrine permanently and celecoxib as needed. We conclude high rate response analyzing literature data and our case to combined therapy: arthroscopic or open surgery followed by RT along with complimentary pharmacotherapy. J Med Cases. 2014;5(3):147-151 doi: http://dx.doi.org/10.14740/jmc1656e

SHPS-1/SIRP1α contributes to interleukin-6 signalling

The transmembrane glycoprotein signal regulatory protein/SHP2-substrate (SIRP1α/SHPS-1) has been implicated in growth factor- and cell adhesion-induced signalling. Here we report on the contribution of SIRP1α to IL-6 type cytokine signalling. SIRP1α binds the protein tyrosine phosphatase SHP2 upon treatment with interleukin-6 in a stimulation-dependent manner. Mouse embryonic fibroblasts expressing a SIRP1α protein which lacks the intracellular part show enhanced SHP2 phosphorylation and ERK1/2 activation in response to IL-6, suggesting that SIRP1α affects IL-6-signalling through SHP2. Whereas SHP2 phosphorylation is enhanced in SIRP1α-deficient cells STAT3 activation is delayed and STAT3-dependent gene induction is reduced which correlates with reduced STAT3 serine phosphorylation. Our results indicate that SIRP1α contributes to IL-6 signalling by counteracting SHP2 phosphorylation which consequently affects ERK-activation and STAT3-dependent transactivation as well as target gene expression. Our observations will help to understand the tight balance of MAPK- and STAT3-activation in response to IL-6 which was found to be misbalanced in many autoimmune diseases, inflammatory proliferative diseases and cancer.

IL-6 signal transduction and its physiological roles: the signal orchestration model.

Interleukin (IL)-6 is a pleiotropic cytokine that not only affects the immune system, but also acts in other biological systems and many physiological events in various organs. In a target cell, IL-6 can simultaneously generate functionally distinct or sometimes contradictory signals through its receptor complex, IL-6Ralpha and gp130. One good illustration is derived from the in vitro observations that IL-6 promotes the growth arrest and differentiation of M1 cells through gp130-mediated STAT3 activation, whereas the Y759/SHP-2-mediated cascade by gp130 stimulation has growth-enhancing effects. The final physiological output can be thought of as a consequence of the orchestration of the diverse signaling pathways generated by a given ligand. This concept, the signal orchestration model, may explain how IL-6 can elicit proinflammatory or anti-inflammatory effects, depending on the in vivo environmental circumstances. Elucidation of the molecular mechanisms underlying this issue is a challenging subject for future research. Intriguingly, recent in vivo studies indicated that the SHP-2-binding site- and YXXQ-mediated pathways through gp130 are not mutually exclusive but affect each other: a mutation at the SHP-2-binding site prolongs STAT3 activation, and a loss of STAT activation by gp130 truncation leads to sustained SHP-2/ERK MAPK phosphorylation. Although IL-6/gp130 signaling is a promising target for drug discovery for many human diseases, the interdependence of each signaling pathway may be an obstacle to the development of a nonpeptide orally active small molecule to inhibit one of these IL-6 signaling cascades, because it would disturb the signal orchestration. In mice, a consequence of the imbalanced signals causes unexpected results such as gastrointestinal disorders, autoimmune diseases, and/or chronic inflammatory proliferative diseases. However, lessons learned from IL-6 KO mice indicate that IL-6 is not essential for vital biological processes, but a significant impact on disease progression in many experimental models for human disorders. Thus, IL-6/gp130 signaling will become a more attractive therapeutic target for human inflammatory diseases when a better understanding of IL-6 signaling, including the identification of the conductor for gp130 signal transduction, is achieved.