J. Fernando Bazan on Cytokine Discoveries
Fast Moving Front Commentary, July 2010
|
Article: IL-33, an interleukin-1-like cytokine that signals via the IL-1 receptor-related protein ST2 and induces T helper type 2-associated cytokines:
|
J. Fernando Bazan talks with ScienceWatch.com and answers a few questions about this month's Fast Moving Fronts paper in the field of Immunology.
Why do you think your paper is highly
cited?
The discovery of IL-33 in 2005 (part of a long-standing and productive collaboration with my former DNAX colleague, Rob Kastelein) broke a logjam in the field caused by the great difficulty that researchers were having at deciphering the function and therapeutic promise of ST2, an orphan IL-1 family receptor (characterized in 1991 by Tominaga) that was enriched on the surface of T-helper-2 (Th2)-type cells.
Defining a novel IL-1 family cytokine as the bona fide ligand of ST2 drove the recognition that ST2 likely functions as a true cytokine receptor, though the publication of its accessory receptor partner (IL-1RAcP) by the DNAX team would not be reported until 2007. There has been a steady growth of interest in IL-33 as more groups have contributed new facets to its biological picture, particularly in how it may be involved in disease processes (like asthma or allergy) that rely on the overproduction of Th2-type cytokines (like IL-4, IL-5 and IL-13).
Even more recently, several groups have reported a discrete cell subset in mice and humans that seems uniquely responsive to IL-33 and also IL-25, an IL-17 family cytokine, with clear implications for therapeutic attack.
Does it describe a new discovery, methodology, or
synthesis of knowledge?
IL-33 followed on the heels of two other seminal cytokine discoveries at DNAX, IL-23 and IL-27, two composite hematopoietic cytokines of the IL-6 family that lay the groundwork for a new and now extremely active field of immunology centered on Th17-type cells, critically involved in chronic inflammatory diseases.
We used the same bottoms-up methodology to tackle the orphan ST2 receptor problem, namely, focus on the predicted architectural design of the likely IL-1 family ligand (a C-terminal beta-trefoil fold preceded by an N-terminal prodomain that ended at a presumptive Caspase-1 cleavage site) and utilized sensitive computational tools to ferret out the best candidate sequence from the emerging genomic databases.
"This paper discusses biological and preclinical data on the relevance of small-molecule cyclin-dependent kinase (CDK) inhibitors for cancer therapy."
I tried a number of bioinformatic approaches, honing their ability to peer into the "twilight zone" of sequence similarity, until finally the sequence of the canine ortholog of IL-33 (then named DVS-27, product of an overexpressed gene in dogs after traumatic brain injury) revealed itself to be an orphan, cryptic IL-1 family member. My postdoc, Jochen Schmitz, immediately cloned out the human ortholog and proceeded to show that it bound the ST2 receptor. So wet bench experiments followed the computational lead.
Would you summarize the significance of your paper
in layman's terms?
Cytokines are some of the key chemical messengers between cells, secreted by (or presented on the surface of) one cell type and binding specifically to receptors on another cell surface, triggering a signal cascade that changes the developmental stage or host defense posture of that latter cell.
In the most recent perspective on IL-33's biological impact, Bob Coffman (Science 328[5982]: 1116-7, 28 May 2010) shows how IL-33 production by epithelial cells in the lung or gut is triggered by parasite attack or allergen exposure, and in turn ends up driving a strong Th2-type immune response. So IL-33 joins a distinguished pantheon of two other IL-1 family cytokines that play critical roles in immune defense, IL-1b and IL-18.
How did you become involved in this research, and
how would you describe the particular challenges, setbacks, and
successes that you've encountered along the way?
DNAX was a cytokine factory at the time, a very exciting place at the cutting edge of immunology, and we had a lot of backing for this type of cross-disciplinary cytokine-hunting work that could perhaps not have occurred at another institute or academic venue. In retrospect, we took a very direct route to solving the ST2 puzzle by making a simplifying assumption that the ligand would be of a particular structural design, and then we used our computational savvy to get straight to an answer—that ended up being correct.
Where do you see your research leading in the
future?
I have stayed connected to IL-33 by contributing at the structural end of things, collaborating with Andreas Lingel, a very bright postdoc in Wayne Fairbrother's group at Genentech, to present a possible model (generated by structure prediction, molecular docking, small-angle X-ray scattering or SAXS, and NMR methods) for the IL-33 ternary receptor complex. This work was published in 2009 in the journal Structure.
I am also keenly aware that there remain a few more orphan receptors in the IL-1 receptor family, suggesting that there still may be some errant IL-1-type ligands hiding in the proteome; alternatively, one or more of the present clan of eleven IL-1 cytokines could be repurposed. So the work continues!
Do you foresee any social or political implications for
your research?
I would hope that my research has its most direct implications in the
clinic, for treatments of severe human disorders. (And I guess that would
be a social implication...)
J. Fernando Bazan, Ph.D.
Senior Scientist
Depts. of Protein Engineering and Structural Biology, Immunology,
and Molecular Biology
Genentech
South San Francisco, CA, USA
KEYWORDS: IL-33, CYTOKINES; NF-KAPPA-B, ACUTE EXACERBATION, EFFECTOR FUNCTION, IMMUNE-RESPONSES, TH2 CELLS, IN VIVO, T1/ST2, FAMILY, IDENTIFICATION, EXPRESSION.