Interleukin-11: review of molecular, cell biology, and clinical use.

F weights of recombinant human (rh) and murine IL-11 are 19,144 daltons and 19,154 daltons, respectively. Mature IRST ISOLATED IN 1990, interleukin-11 (IL-11) has proven to be a fascinating cytokine with pleiotropic effects on multiple tissues. Initially characterized as a hemahuman and primate IL-11 protein share 94% identity whereas human and murine proteins share 88% identity in the amino topoietic cytokine with thrombopoietic activity, IL-11 has now been shown to be expressed and have activity in multiacid sequence. Although IL-11 is rich in proline residues (12%) and lacks cysteine residues (ie, lacks potential disulple other tissues, including brain, spinal cord neurons, gut, and testis. Yet to date, the physiologic role of this protein fide bonds), hIL-11 is highly helical (57% { 1%) and is thermally stable (melting temperature [Tm] Å 907C). Acremains unknown. Our laboratory has recently generated a mutated allele of IL-11 in the mouse germline (X.D. and cording to the structural model proposed by Czupryn et al, IL-11 contains a four-helix bundle topology (denoted A-D) D.A.W., unpublished results, January 1997) and future studies of homozygous IL-11–deficient mice derived from these whereby methionine residue 58 (Met) and lysines (Lys and Lys) are located on the surface of the protein. Chemical founder animals should illuminate the function(s) of this protein in vivo. In this article, we update current understandmodifications (alkylation or site-directed mutagenesis) of the Met residue results in a 25-fold decrease in in vitro bioacing of the biology of IL-11, concentrating on data published after the last comprehensive review published in 1994. tivity of rhIL-11. Chemical modification of the Lys and Lys results in a 3-fold decrease in bioactivity. rhIL-11 CLONING AND GENOMIC CHARACTERIZATION lacking the four carboxyl-terminal residues has a 25-fold Human IL-11 was cloned in 1990 and details of this clonlower bioactivity and elimination of 8 or more carboxyling and early work on IL-11 have been summarized preterminal residues completely abolishes activity. The C-terviously. More recently the murine IL-11 cDNA was cloned minus of rhIL-11 is predicted to be helical and to be involved using an expression library generated from a lipopolysacchain the primary receptor binding site (site I). Important resiride (LPS)-induced murine fetal thymic cell line (T2). The dues contributing to receptor binding in this site include murine IL-11 cDNA shares 80% homology with human ILArg, His, Asp, Trp, and Arg. Met is potentially 11 at the nucleotide level. Both human and murine IL-11 involved in the receptor binding. In the region between Pro genomic sequences consist of 5 exons and 4 introns and and Lys, there are a number of residues (including Pro, have been mapped to chromosome 19 at band 19q13.3-q13.4 Glu, Leu, Leu, Arg, Leu, Thr, Arg, Leu, and and to the centromeric region of chromosome 7, respecArg) that are critical for the bioactivity of IL-11 and may tively (and M. McAndrew-Hill and D.A.W., unpublished constitute part of a gp130 binding site (site II). Lys and results, June 1996). The 5*-flanking region of the human Lys, as well as positively charged arginine residues, which IL-11 gene contains several DNA motifs postulated to be involved in transcriptional control. A ‘‘TATA’’ box-like sequence, TATATAA, is located 180 nucleotides upstream From James Whitcomb Riley Hospital for Children, Section of Hematology/Oncology, Herman B Wells Center for Pediatric Refrom the translation initiation codon ATG. A 10-bp prosearch, and Howard Hughes Medical Institute, Indiana University moter sequence (5* GGTGAGTCAG 3*) in this region conSchool of Medicine, Indianapolis. tains an activator protein-1 (AP-1) site (underlined). JunD/ Submitted October 28, 1996; accepted January 15, 1997. AP-1 complexes are responsible for the basal-level transcripX.D. is supported by Grant-in-Aid No. 95-6, Riley Memorial tion of IL-11 gene in bone marrow (BM) fibroblast cells. Association. D.A.W. receives payments from Children’s Hospital, There are two polyadenylation sites located in the 3* untransBoston, MA, based on certain milestones set forth in an IL-11 agreelated region (UTR) at nucleotide positions 6762 and 5591 ment between Genetics Institute, Cambridge, MA, and Children’s and these alternative sites give rise to the 2.5and 1.5-kb Hospital. IL-11 mRNA transcripts expressed in several IL-1a–inAddress reprint requests to David A. Williams, MD, Herman B duced cell lines. Wells Center for Pediatric Research, James Whitcomb Riley Hospital for Children, 702 Barnhill Dr, Room #2600, Indianapolis, IN PROTEIN CHARACTERIZATION 46202-5225. IL-11 precursor protein consists of 199 amino acids (aa), q 1997 by The American Society of Hematology. 0006-4971/97/8911-0011$3.00/0 including a 21-aa leader sequence. The theoretical molecular