Macrophage migration inhibitory factor (MIF) is a pro-inflammatory mediator with the ability to induce various immunomodulatory responses and override glucocorticoid-driven immunosuppression. Some of these functions have been linked to the unusual enzymatic properties of the protein, namely tautomerase and oxidoreductase activities. However, there are conflicting reports regarding the functional role of these enzymatic properties in normal physiological homeostasis and disease progression. Therefore, we have produced a highly pure, virtually endotoxin-free recombinant MIF preparation and fully characterized this using a variety of biochemical and biophysical approaches. The recombinant protein, with demonstrable enzymatic activity, was then used to systematically examine the biological activity of MIF. Surprisingly, treatment with MIF alone failed to induce cytokine expression, with the exception of IL-8. However, co-treatment of lipopolysaccharide (LPS) in conjunction with MIF produced synergistic secretion of tumor necrosis factor-␣, interleukin (IL)-1, and IL-8 compared with LPS alone. The potentiating effect of MIF was seen at physiologically relevant concentrations. These data suggest that MIF has no conventional cytokine activity but, rather, acts to modulate and amplify the response to LPS. MIF2 is a highly evolutionarily conserved 12.5-kDa protein that was assigned a unique combination of hormone-like, cytokine, and thioredoxin-like properties (1). Significant interest in MIF as a pro-inflammatory mediator involved in human disease was based on the following important findings: (i) raised MIF concentrations in peripheral blood and specific tissue specimens in a broad range of diseases, including inflammatory conditions, various tumors, and metabolic disorders such as atherosclerosis, diabetes, and obesity (2-7); (ii) genetic evidence of linkage with juvenile idiopathic arthritis (8), rheumatoid arthritis (9); (iii) neutralization of MIF by anti-MIF antibodies, shown to be therapeutically beneficial in a variety of animal models of inflammatory diseases, including sepsis, rheumatoid arthritis, pulmonary infections, and atherosclerosis (4, 7, 9, 10).MIF has no homology with any other pro-inflammatory cytokines, and the mechanism(s) by which MIF exerts its biological effects remain unclear. Attempts to identify a cell surface MIF transmembrane receptor, which would explain some of the reported MIF regulatory effects in relation to extracellular signal-regulated protein kinase-1/2 (11), synovial cell p38 kinase (12), and p53 (13, 14), have been unsuccessful. CD74 (invariant polypeptide of MHC type II) was found to be a putative MIF receptor (15), although there is no compelling evidence of any potential link between this antigen-processing molecule and intracellular signaling pathways. The absence of a validated signal transduction mechanism via a transmembrane receptor suggests that MIF may mediate its effects mainly by non-receptor mediated endocytosis (16).In contrast to all other known cytokines, MIF has...

CT-P13, the biosimilar of infliximab, has been recently approved in the EU, Australia, Canada, Japan and many other countries. Thus, it was the first biosimilar approved in the field of rheumatology, dermatology and gastroenterology. Since there has been debate about the issue of switching from RMP to the biosimilar and some national societies have expressed concerns, this review was written with the following objectives: The review concludes that whilst prudent switching practices should be employed, growing safety experience accumulated thus far with CT-P13 and other biosimilars is favorable and does not raise any specific concerns.

Macrophage migration inhibitory factor (MIF) has an amazing history of rediscoveries and controversies surroundings its true biological function. It has been classified as a powerful cytokine capable of inducing tumour necrosis factor (TNF)-a, IL-1b, IL-6, IL-8, PGE2 along with its ability to override glucocorticoid activity in relation to TNF-a release from monocytes. However, our recent study has failed to reproduce findings on MIF as a factor with cytokine-inducing properties but it has confirmed that MIF is capable of inducing glucocorticoid-counter regulating activity and amplifying LPS-driven cytokine responses. The aim of this review is to analyse the plethora of data surrounding MIF not just as a cytokine, but also as a hormone-like molecule, enzyme with atypical properties and as a thioredoxin-like protein to address fundamental questions about MIF functionality.

No abstract

A rapid growth of investment into clinical research and new drug development has manifested itself by an exponential increase of new products coming onto the worldwide market. The emerging pharmaceutical and biotech markets in Southeast Asia are believed to be extremely promising from a commercial point of view in the next decade. The unique position of the Asian market and the diversity in clinical research initiatives are linked with diverse regulatory requirements for clinical development and registration of new medicines. Some of these differences have an impact on timelines for marketing authorizations in South Korea, China, Thailand, Japan, Singapore, and other countries. One of the approaches to streamlining regulatory strategy in different countries is the initiation of multicountry international clinical trials trying to address requirements and allowing registration in several regional countries simultaneously. Increasing cooperation between South Asian countries in relation to regulatory requirements and clinical development will facilitate the registration of innovative medicines in this rapidly developing region of the world and enable improved cohesiveness between countries in a drug safety framework.