F weights of recombinant human (rh) and murine IL-11 are 19,144 daltons6 and 19,154 daltons, 2 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 hema- human 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 multi- acid sequence. 2, 6, 7 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 90C). 8 Acremains unknown. Our laboratory has recently generated a mutated allele of IL-11 in the mouse germline (XD and cording to the structural model proposed by Czupryn et al, 8 IL-11 contains a four-helix bundle topology (denoted AD) DAW, unpublished results, January 1997) and future studies of homozygous IL-11–deficient mice derived from these whereby methionine residue 58 (Met58) and lysines (Lys41 and Lys98) 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 understand- modifications (alkylation or site-directed mutagenesis) of the Met58 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. 1 tivity of rhIL-11. Chemical modification of the Lys41 and Lys98 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 clon- lower bioactivity and elimination of 8 or more carboxyling and early work on IL-11 have been summarized pre- terminal residues completely abolishes activity. 9 The C-terviously. 1 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 lipopolysaccha- in the primary receptor binding site (site I). Important resiride (LPS)-induced murine fetal thymic cell line (T2). 2 The dues contributing to receptor binding in this site include murine IL-11 cDNA shares 80% homology with human IL- Arg150, His153, Asp164, Trp165, and Arg168. 8 Met58 is potentially 11 at the nucleotide level. 2 Both human and murine IL-11 involved in the receptor binding. In the region between Pro13 genomic sequences consist of 5 exons and 4 introns and and Lys41, there are a number of residues (including Pro13, have been mapped to chromosome 19 at band 19q13. 3-q13. 4 Glu16, Leu17, Leu22, Arg25, Leu28, Thr31, Arg32, Leu34, and and to the centromeric region of chromosome 7, respec- Arg39) that are critical for the bioactivity of IL-11 and may tively2, 3 (and M. McAndrew-Hill and DAW, unpublished constitute part of a gp130 binding site (site II). 8 Lys41 and results, June 1996). The 5-flanking region of the human Lys98, as well as positively charged arginine residues, which IL-11 gene contains several DNA motifs postulated to be